19-10986523-CGGCCCTGGCCCTGGCCCT-CGGCCCTGGCCCTGGCCCTGGCCCTGGCCCT

Variant names:

• chr19-10986523-C-CGGCCCTGGCCCT
• rs372601826
• NM_001387283.1:c.702_713dupTGGCCCTGGCCC

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP3 BP6

The NM_001387283.1(SMARCA4):​c.702_713dupTGGCCCTGGCCC​(p.Pro238_Gly239insGlyProGlyPro) variant causes a disruptive inframe insertion change. The variant allele was found at a frequency of 0.0000013 in 1,543,526 control chromosomes in the GnomAD database, with no homozygous occurrence. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. P238P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
• Consequence: SMARCA4 NM_001387283.1 disruptive_inframe_insertion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:1
• Conservation: PhyloP100: 6.83
• Publications: 1 publications found

Genes affected

SMARCA4 (HGNC:11100): (SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily a, member 4) The protein encoded by this gene is a member of the SWI/SNF family of proteins and is similar to the brahma protein of Drosophila. Members of this family have helicase and ATPase activities and are thought to regulate transcription of certain genes by altering the chromatin structure around those genes. The encoded protein is part of the large ATP-dependent chromatin remodeling complex SNF/SWI, which is required for transcriptional activation of genes normally repressed by chromatin. In addition, this protein can bind BRCA1, as well as regulate the expression of the tumorigenic protein CD44. Mutations in this gene cause rhabdoid tumor predisposition syndrome type 2. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, May 2012]

SMARCA4 Gene-Disease associations (from GenCC):

• Coffin-Siris syndrome

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet, Illumina
• intellectual disability, autosomal dominant 16

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
• rhabdoid tumor predisposition syndrome 2

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, ClinGen, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), G2P
• uterine corpus sarcoma

  Inheritance: AR Classification: MODERATE Submitted by: Genomics England PanelApp
• familial rhabdoid tumor

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• hereditary nonpolyposis colon cancer

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_001387283.1
• BP6: Variant 19-10986523-C-CGGCCCTGGCCCT is Benign according to our data. Variant chr19-10986523-C-CGGCCCTGGCCCT is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 826778. Variant chr19-10986523-C-CGGCCCTGGCCCT is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 826778. Variant chr19-10986523-C-CGGCCCTGGCCCT is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 826778. Variant chr19-10986523-C-CGGCCCTGGCCCT is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 826778. Variant chr19-10986523-C-CGGCCCTGGCCCT is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 826778. Variant chr19-10986523-C-CGGCCCTGGCCCT is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 826778. Variant chr19-10986523-C-CGGCCCTGGCCCT is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 826778. Variant chr19-10986523-C-CGGCCCTGGCCCT is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 826778. Variant chr19-10986523-C-CGGCCCTGGCCCT is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 826778. Variant chr19-10986523-C-CGGCCCTGGCCCT is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 826778. Variant chr19-10986523-C-CGGCCCTGGCCCT is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 826778. Variant chr19-10986523-C-CGGCCCTGGCCCT is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 826778. Variant chr19-10986523-C-CGGCCCTGGCCCT is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 826778. Variant chr19-10986523-C-CGGCCCTGGCCCT is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 826778. Variant chr19-10986523-C-CGGCCCTGGCCCT is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 826778. Variant chr19-10986523-C-CGGCCCTGGCCCT is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 826778. Variant chr19-10986523-C-CGGCCCTGGCCCT is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 826778. Variant chr19-10986523-C-CGGCCCTGGCCCT is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 826778. Variant chr19-10986523-C-CGGCCCTGGCCCT is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 826778. Variant chr19-10986523-C-CGGCCCTGGCCCT is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 826778. Variant chr19-10986523-C-CGGCCCTGGCCCT is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 826778. Variant chr19-10986523-C-CGGCCCTGGCCCT is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 826778. Variant chr19-10986523-C-CGGCCCTGGCCCT is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 826778. Variant chr19-10986523-C-CGGCCCTGGCCCT is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 826778. Variant chr19-10986523-C-CGGCCCTGGCCCT is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 826778. Variant chr19-10986523-C-CGGCCCTGGCCCT is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 826778. Variant chr19-10986523-C-CGGCCCTGGCCCT is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 826778. Variant chr19-10986523-C-CGGCCCTGGCCCT is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 826778. Variant chr19-10986523-C-CGGCCCTGGCCCT is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 826778. Variant chr19-10986523-C-CGGCCCTGGCCCT is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 826778. Variant chr19-10986523-C-CGGCCCTGGCCCT is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 826778. Variant chr19-10986523-C-CGGCCCTGGCCCT is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 826778. Variant chr19-10986523-C-CGGCCCTGGCCCT is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 826778. Variant chr19-10986523-C-CGGCCCTGGCCCT is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 826778. Variant chr19-10986523-C-CGGCCCTGGCCCT is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 826778. Variant chr19-10986523-C-CGGCCCTGGCCCT is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 826778. Variant chr19-10986523-C-CGGCCCTGGCCCT is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 826778. Variant chr19-10986523-C-CGGCCCTGGCCCT is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 826778. Variant chr19-10986523-C-CGGCCCTGGCCCT is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 826778. Variant chr19-10986523-C-CGGCCCTGGCCCT is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 826778. Variant chr19-10986523-C-CGGCCCTGGCCCT is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 826778. Variant chr19-10986523-C-CGGCCCTGGCCCT is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 826778. Variant chr19-10986523-C-CGGCCCTGGCCCT is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 826778. Variant chr19-10986523-C-CGGCCCTGGCCCT is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 826778. Variant chr19-10986523-C-CGGCCCTGGCCCT is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 826778. Variant chr19-10986523-C-CGGCCCTGGCCCT is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 826778. Variant chr19-10986523-C-CGGCCCTGGCCCT is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 826778. Variant chr19-10986523-C-CGGCCCTGGCCCT is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 826778. Variant chr19-10986523-C-CGGCCCTGGCCCT is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 826778. Variant chr19-10986523-C-CGGCCCTGGCCCT is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 826778. Variant chr19-10986523-C-CGGCCCTGGCCCT is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 826778. Variant chr19-10986523-C-CGGCCCTGGCCCT is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 826778. Variant chr19-10986523-C-CGGCCCTGGCCCT is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 826778. Variant chr19-10986523-C-CGGCCCTGGCCCT is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 826778. Variant chr19-10986523-C-CGGCCCTGGCCCT is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 826778. Variant chr19-10986523-C-CGGCCCTGGCCCT is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 826778. Variant chr19-10986523-C-CGGCCCTGGCCCT is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 826778. Variant chr19-10986523-C-CGGCCCTGGCCCT is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 826778. Variant chr19-10986523-C-CGGCCCTGGCCCT is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 826778. Variant chr19-10986523-C-CGGCCCTGGCCCT is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 826778. Variant chr19-10986523-C-CGGCCCTGGCCCT is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 826778. Variant chr19-10986523-C-CGGCCCTGGCCCT is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 826778. Variant chr19-10986523-C-CGGCCCTGGCCCT is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 826778. Variant chr19-10986523-C-CGGCCCTGGCCCT is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 826778. Variant chr19-10986523-C-CGGCCCTGGCCCT is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 826778. Variant chr19-10986523-C-CGGCCCTGGCCCT is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 826778. Variant chr19-10986523-C-CGGCCCTGGCCCT is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 826778. Variant chr19-10986523-C-CGGCCCTGGCCCT is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 826778. Variant chr19-10986523-C-CGGCCCTGGCCCT is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 826778. Variant chr19-10986523-C-CGGCCCTGGCCCT is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 826778. Variant chr19-10986523-C-CGGCCCTGGCCCT is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 826778. Variant chr19-10986523-C-CGGCCCTGGCCCT is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 826778. Variant chr19-10986523-C-CGGCCCTGGCCCT is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 826778. Variant chr19-10986523-C-CGGCCCTGGCCCT is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 826778. Variant chr19-10986523-C-CGGCCCTGGCCCT is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 826778. Variant chr19-10986523-C-CGGCCCTGGCCCT is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 826778. Variant chr19-10986523-C-CGGCCCTGGCCCT is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 826778.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMARCA4	NM_001387283.1	c.702_713dupTGGCCCTGGCCC	p.Pro238_Gly239insGlyProGlyPro	disruptive_inframe_insertion	Exon 4 of 36	ENST00000646693.2	NP_001374212.1
SMARCA4	NM_003072.5	c.702_713dupTGGCCCTGGCCC	p.Pro238_Gly239insGlyProGlyPro	disruptive_inframe_insertion	Exon 4 of 35	ENST00000344626.10	NP_003063.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMARCA4	ENST00000646693.2	c.702_713dupTGGCCCTGGCCC	p.Pro238_Gly239insGlyProGlyPro	disruptive_inframe_insertion	Exon 4 of 36		NM_001387283.1	ENSP00000495368.1
SMARCA4	ENST00000344626.10	c.702_713dupTGGCCCTGGCCC	p.Pro238_Gly239insGlyProGlyPro	disruptive_inframe_insertion	Exon 4 of 35	1	NM_003072.5	ENSP00000343896.4
SMARCA4	ENST00000643549.1	c.702_713dupTGGCCCTGGCCC	p.Pro238_Gly239insGlyProGlyPro	disruptive_inframe_insertion	Exon 4 of 35			ENSP00000493975.1
SMARCA4	ENST00000541122.6	c.702_713dupTGGCCCTGGCCC	p.Pro238_Gly239insGlyProGlyPro	disruptive_inframe_insertion	Exon 5 of 35	5		ENSP00000445036.2
SMARCA4	ENST00000643296.1	c.702_713dupTGGCCCTGGCCC	p.Pro238_Gly239insGlyProGlyPro	disruptive_inframe_insertion	Exon 4 of 34			ENSP00000496635.1
SMARCA4	ENST00000644737.1	c.702_713dupTGGCCCTGGCCC	p.Pro238_Gly239insGlyProGlyPro	disruptive_inframe_insertion	Exon 4 of 34			ENSP00000495548.1
SMARCA4	ENST00000589677.5	c.702_713dupTGGCCCTGGCCC	p.Pro238_Gly239insGlyProGlyPro	disruptive_inframe_insertion	Exon 5 of 35	5		ENSP00000464778.1
SMARCA4	ENST00000643995.1	c.114_125dupTGGCCCTGGCCC	p.Pro42_Gly43insGlyProGlyPro	disruptive_inframe_insertion	Exon 1 of 32			ENSP00000496004.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152200 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 7.19e-7 AC: 1 AN: 1391208 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 686496

African (AFR) AF: 0.00 AC: 0 AN: 31580

American (AMR) AF: 0.00 AC: 0 AN: 35666

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25116

East Asian (EAS) AF: 0.0000280 AC: 1 AN: 35728

South Asian (SAS) AF: 0.00 AC: 0 AN: 79182

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 41640

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5694

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1078664

Other (OTH) AF: 0.00 AC: 0 AN: 57938

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152318 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74474

African (AFR) AF: 0.00 AC: 0 AN: 41574

American (AMR) AF: 0.00 AC: 0 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68024

Other (OTH) AF: 0.00 AC: 0 AN: 2114

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Rhabdoid tumor predisposition syndrome 2 Uncertain:2

Jan 18, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. ClinVar contains an entry for this variant (Variation ID: 826778). This variant has not been reported in the literature in individuals affected with SMARCA4-related conditions. This variant is not present in population databases (gnomAD no frequency). This variant, c.702_713dup, results in the insertion of 4 amino acid(s) of the SMARCA4 protein (p.Gly241_Pro244dup), but otherwise preserves the integrity of the reading frame. -

Oct 31, 2023

Baylor Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome Uncertain:1 Benign:1

Apr 13, 2021

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Jul 13, 2021

Sema4, Sema4

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: curation

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		6.8
Mutation Taster		=80/20	polymorphism

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs372601826; hg19: chr19-11097199;