rs750556885

Variant names:

• chr19-11058300-G-A
• rs750556885
• NM_001387283.1:c.4566G>A

Your query was ambiguous. Multiple possible variants found:

• chr19-11058300-G-A
• chr19-11058300-G-C
• chr19-11058300-G-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_003072.5(SMARCA4):​c.4470G>A​(p.Ser1490Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000438 in 1,461,284 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 Likely benign (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000044 (0 hom.)
• Consequence: SMARCA4 NM_003072.5 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -3.27

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]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.52).
• BP6: Variant 19-11058300-G-A is Benign according to our data. Variant chr19-11058300-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 415164.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-3.27 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4_exome allele frequency = 0.0000438 (64/1461284) while in subpopulation NFE AF= 0.0000558 (62/1111914). AF 95% confidence interval is 0.0000444. There are 0 homozygotes in gnomad4_exome. There are 26 alleles in male gnomad4_exome subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAdExome4 at 64 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMARCA4	NM_001387283.1	c.4566G>A	p.Ser1522Ser	synonymous_variant	Exon 32 of 36	ENST00000646693.2	NP_001374212.1
SMARCA4	NM_003072.5	c.4470G>A	p.Ser1490Ser	synonymous_variant	Exon 31 of 35	ENST00000344626.10	NP_003063.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMARCA4	ENST00000646693.2	c.4566G>A	p.Ser1522Ser	synonymous_variant	Exon 32 of 36		NM_001387283.1	ENSP00000495368.1
SMARCA4	ENST00000344626.10	c.4470G>A	p.Ser1490Ser	synonymous_variant	Exon 31 of 35	1	NM_003072.5	ENSP00000343896.4
SMARCA4	ENST00000643549.1	c.4476G>A	p.Ser1492Ser	synonymous_variant	Exon 31 of 35			ENSP00000493975.1
SMARCA4	ENST00000541122.6	c.4380G>A	p.Ser1460Ser	synonymous_variant	Exon 31 of 35	5		ENSP00000445036.2
SMARCA4	ENST00000643296.1	c.4380G>A	p.Ser1460Ser	synonymous_variant	Exon 30 of 34			ENSP00000496635.1
SMARCA4	ENST00000644737.1	c.4380G>A	p.Ser1460Ser	synonymous_variant	Exon 30 of 34			ENSP00000495548.1
SMARCA4	ENST00000589677.5	c.4377G>A	p.Ser1459Ser	synonymous_variant	Exon 31 of 35	5		ENSP00000464778.1
SMARCA4	ENST00000643995.1	c.3891G>A	p.Ser1297Ser	synonymous_variant	Exon 28 of 32			ENSP00000496004.1
SMARCA4	ENST00000644963.1	c.3120G>A	p.Ser1040Ser	synonymous_variant	Exon 24 of 28			ENSP00000495599.1
SMARCA4	ENST00000644065.1	c.3102G>A	p.Ser1034Ser	synonymous_variant	Exon 23 of 27			ENSP00000493615.1
SMARCA4	ENST00000642350.1	c.2964G>A	p.Ser988Ser	synonymous_variant	Exon 23 of 27			ENSP00000495355.1
SMARCA4	ENST00000643857.1	c.2832G>A	p.Ser944Ser	synonymous_variant	Exon 22 of 25			ENSP00000494159.1
SMARCA4	ENST00000538456.4	c.636G>A	p.Ser212Ser	synonymous_variant	Exon 5 of 8	3		ENSP00000495197.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000120 AC: 3 AN: 250956 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135824

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000578

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000881

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000438 AC: 64 AN: 1461284 Hom.: 0 Cov.: 32 AF XY: 0.0000358 AC XY: 26 AN XY: 726992

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000558

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.0000529

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Rhabdoid tumor predisposition syndrome 2 Benign:1

Dec 22, 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

Sep 24, 2015

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. -

SMARCA4-related disorder Benign:1

Aug 10, 2022

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.52
CADD	Benign	0.71
DANN	Benign	0.78
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs750556885; hg19: chr19-11168976;