19-11058847-C-T

Variant names:

• chr19-11058847-C-T
• rs757189400
• NM_001387283.1:c.4689C>T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Moderate BP6 BP7

The NM_001387283.1(SMARCA4):​c.4689C>T​(p.Leu1563Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000479 in 1,461,804 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: SMARCA4 NM_001387283.1 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: 1.64
• 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 -4 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.33).
• BP6: Variant 19-11058847-C-T is Benign according to our data. Variant chr19-11058847-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 436808.We mark this variant Likely_benign, oryginal submission is: [Conflicting_classifications_of_pathogenicity].
• BP7: Synonymous conserved (PhyloP=1.64 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMARCA4	NM_001387283.1	c.4689C>T	p.Leu1563Leu	synonymous_variant	Exon 33 of 36	ENST00000646693.2	NP_001374212.1
SMARCA4	NM_003072.5	c.4593C>T	p.Leu1531Leu	synonymous_variant	Exon 32 of 35	ENST00000344626.10	NP_003063.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMARCA4	ENST00000646693.2	c.4689C>T	p.Leu1563Leu	synonymous_variant	Exon 33 of 36		NM_001387283.1	ENSP00000495368.1
SMARCA4	ENST00000344626.10	c.4593C>T	p.Leu1531Leu	synonymous_variant	Exon 32 of 35	1	NM_003072.5	ENSP00000343896.4
SMARCA4	ENST00000643549.1	c.4599C>T	p.Leu1533Leu	synonymous_variant	Exon 32 of 35			ENSP00000493975.1
SMARCA4	ENST00000541122.6	c.4503C>T	p.Leu1501Leu	synonymous_variant	Exon 32 of 35	5		ENSP00000445036.2
SMARCA4	ENST00000643296.1	c.4503C>T	p.Leu1501Leu	synonymous_variant	Exon 31 of 34			ENSP00000496635.1
SMARCA4	ENST00000644737.1	c.4503C>T	p.Leu1501Leu	synonymous_variant	Exon 31 of 34			ENSP00000495548.1
SMARCA4	ENST00000589677.5	c.4500C>T	p.Leu1500Leu	synonymous_variant	Exon 32 of 35	5		ENSP00000464778.1
SMARCA4	ENST00000643995.1	c.4014C>T	p.Leu1338Leu	synonymous_variant	Exon 29 of 32			ENSP00000496004.1
SMARCA4	ENST00000644963.1	c.3243C>T	p.Leu1081Leu	synonymous_variant	Exon 25 of 28			ENSP00000495599.1
SMARCA4	ENST00000644065.1	c.3225C>T	p.Leu1075Leu	synonymous_variant	Exon 24 of 27			ENSP00000493615.1
SMARCA4	ENST00000642350.1	c.3087C>T	p.Leu1029Leu	synonymous_variant	Exon 24 of 27			ENSP00000495355.1
SMARCA4	ENST00000643857.1	c.2895+484C>T		intron_variant	Intron 22 of 24			ENSP00000494159.1
SMARCA4	ENST00000538456.4	c.699+484C>T		intron_variant	Intron 5 of 7	3		ENSP00000495197.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000159 AC: 4 AN: 251384 AF XY: 0.0000147

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000264

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000479 AC: 7 AN: 1461804 Hom.: 0 Cov.: 31 AF XY: 0.00000550 AC XY: 4 AN XY: 727210

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53368

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000450 AC: 5 AN: 1111984

Other (OTH) AF: 0.0000166 AC: 1 AN: 60394

GnomAD4 genome Cov.: 32

Alfa AF: 0.000111 Hom.: 0

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1

Nov 08, 2016

Genetic Services Laboratory, University of Chicago

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Intellectual disability, autosomal dominant 16 Benign:1

Jul 15, 2021

Genome-Nilou Lab

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Rhabdoid tumor predisposition syndrome 2 Benign:1

Dec 17, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome Benign:1

Apr 03, 2019

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.33
CADD	Benign	5.8
DANN	Benign	0.77
PhyloP100		1.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=85/15	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs757189400; hg19: chr19-11169523;