19-10986535-TGGCCCTGGCCCC-TGGCCCTGGCCCCGGCCCTGGCCCC

Variant names:

• chr19-10986535-T-TGGCCCTGGCCCC
• rs1555753680
• NM_001387283.1:c.708_719dupTGGCCCCGGCCC

Variant summary

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

The NM_001387283.1(SMARCA4):​c.708_719dupTGGCCCCGGCCC​(p.Pro240_Gly241insGlyProGlyPro) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000216 in 1,389,190 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. P240P) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000022 (0 hom.)
• Consequence: SMARCA4 NM_001387283.1 disruptive_inframe_insertion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: 3.52
• Publications: 0 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 19-10986535-T-TGGCCCTGGCCCC is Benign according to our data. Variant chr19-10986535-T-TGGCCCTGGCCCC is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 470452.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMARCA4	NM_001387283.1	c.708_719dupTGGCCCCGGCCC	p.Pro240_Gly241insGlyProGlyPro	disruptive_inframe_insertion	Exon 4 of 36	ENST00000646693.2	NP_001374212.1
SMARCA4	NM_003072.5	c.708_719dupTGGCCCCGGCCC	p.Pro240_Gly241insGlyProGlyPro	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.708_719dupTGGCCCCGGCCC	p.Pro240_Gly241insGlyProGlyPro	disruptive_inframe_insertion	Exon 4 of 36		NM_001387283.1	ENSP00000495368.1
SMARCA4	ENST00000344626.10	c.708_719dupTGGCCCCGGCCC	p.Pro240_Gly241insGlyProGlyPro	disruptive_inframe_insertion	Exon 4 of 35	1	NM_003072.5	ENSP00000343896.4
SMARCA4	ENST00000643549.1	c.708_719dupTGGCCCCGGCCC	p.Pro240_Gly241insGlyProGlyPro	disruptive_inframe_insertion	Exon 4 of 35			ENSP00000493975.1
SMARCA4	ENST00000541122.6	c.708_719dupTGGCCCCGGCCC	p.Pro240_Gly241insGlyProGlyPro	disruptive_inframe_insertion	Exon 5 of 35	5		ENSP00000445036.2
SMARCA4	ENST00000643296.1	c.708_719dupTGGCCCCGGCCC	p.Pro240_Gly241insGlyProGlyPro	disruptive_inframe_insertion	Exon 4 of 34			ENSP00000496635.1
SMARCA4	ENST00000644737.1	c.708_719dupTGGCCCCGGCCC	p.Pro240_Gly241insGlyProGlyPro	disruptive_inframe_insertion	Exon 4 of 34			ENSP00000495548.1
SMARCA4	ENST00000589677.5	c.708_719dupTGGCCCCGGCCC	p.Pro240_Gly241insGlyProGlyPro	disruptive_inframe_insertion	Exon 5 of 35	5		ENSP00000464778.1
SMARCA4	ENST00000643995.1	c.120_131dupTGGCCCCGGCCC	p.Pro44_Gly45insGlyProGlyPro	disruptive_inframe_insertion	Exon 1 of 32			ENSP00000496004.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000216 AC: 3 AN: 1389190 Hom.: 0 Cov.: 34 AF XY: 0.00000146 AC XY: 1 AN XY: 685600

African (AFR) AF: 0.00 AC: 0 AN: 31560

American (AMR) AF: 0.00 AC: 0 AN: 35634

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25120

East Asian (EAS) AF: 0.00 AC: 0 AN: 35722

South Asian (SAS) AF: 0.00 AC: 0 AN: 79126

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39876

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5690

European-Non Finnish (NFE) AF: 0.00000278 AC: 3 AN: 1078554

Other (OTH) AF: 0.00 AC: 0 AN: 57908

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:1 Benign:1

May 17, 2021

Sema4, Sema4

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: curation

- -

Jan 06, 2023

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. -

Rhabdoid tumor predisposition syndrome 2 Uncertain:1

Dec 04, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant, c.708_719dup, 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. This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with SMARCA4-related conditions. ClinVar contains an entry for this variant (Variation ID: 470452). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		3.5

Splicing

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

Other links and lift over

dbSNP: rs1555753680; hg19: chr19-11097211;