rs776431136

Variant names:

• chr19-10991224-G-A
• rs776431136
• NM_001387283.1:c.1320G>A

Your query was ambiguous. Multiple possible variants found:

• chr19-10991224-G-A
• chr19-10991224-G-C

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 2P and 11B. PM2 BP4_Moderate BP6_Very_Strong BP7

The NM_003072.5(SMARCA4):​c.1320G>A​(p.Lys440Lys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,472 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: 33)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: SMARCA4 NM_003072.5 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.01

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 -9 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.38).
• BP6: Variant 19-10991224-G-A is Benign according to our data. Variant chr19-10991224-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 537852.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.01 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMARCA4	NM_001387283.1	c.1320G>A	p.Lys440Lys	synonymous_variant	Exon 8 of 36	ENST00000646693.2	NP_001374212.1
SMARCA4	NM_003072.5	c.1320G>A	p.Lys440Lys	synonymous_variant	Exon 8 of 35	ENST00000344626.10	NP_003063.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMARCA4	ENST00000646693.2	c.1320G>A	p.Lys440Lys	synonymous_variant	Exon 8 of 36		NM_001387283.1	ENSP00000495368.1
SMARCA4	ENST00000344626.10	c.1320G>A	p.Lys440Lys	synonymous_variant	Exon 8 of 35	1	NM_003072.5	ENSP00000343896.4
SMARCA4	ENST00000643549.1	c.1320G>A	p.Lys440Lys	synonymous_variant	Exon 8 of 35			ENSP00000493975.1
SMARCA4	ENST00000541122.6	c.1320G>A	p.Lys440Lys	synonymous_variant	Exon 9 of 35	5		ENSP00000445036.2
SMARCA4	ENST00000643296.1	c.1320G>A	p.Lys440Lys	synonymous_variant	Exon 8 of 34			ENSP00000496635.1
SMARCA4	ENST00000644737.1	c.1320G>A	p.Lys440Lys	synonymous_variant	Exon 8 of 34			ENSP00000495548.1
SMARCA4	ENST00000589677.5	c.1320G>A	p.Lys440Lys	synonymous_variant	Exon 9 of 35	5		ENSP00000464778.1
SMARCA4	ENST00000643995.1	c.732G>A	p.Lys244Lys	synonymous_variant	Exon 5 of 32			ENSP00000496004.1
SMARCA4	ENST00000644065.1	c.48G>A	p.Lys16Lys	synonymous_variant	Exon 1 of 27			ENSP00000493615.1
SMARCA4	ENST00000644963.1	c.-37G>A		upstream_gene_variant				ENSP00000495599.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000803 AC: 2 AN: 249024 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 134842

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

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: 0.0000178

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461472 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 726996

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Rhabdoid tumor predisposition syndrome 2 Benign:1

Nov 24, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome Benign:1

Dec 27, 2018

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	-0.38
CADD	Benign	10
DANN	Benign	0.67
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs776431136; hg19: chr19-11101900;