rs754024829

Positions:

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 2P and 13B. PM2BP4_StrongBP6_Very_StrongBP7

The NM_003072.5(SMARCA4):c.1944G>A(p.Gly648Gly) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000186 in 1,613,702 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

SMARCA4
NM_003072.5 splice_region, synonymous

Scores

Splicing: ADA: 0.0001661

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -1.12

Variant links:

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 links:

SMARCA4 (HGNC:):

SMARCA4 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -11 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.49).

BP6

Variant 19-11003340-G-A is Benign according to our data. Variant chr19-11003340-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 470271.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-1.12 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SMARCA4	NM_001387283.1 linkuse as main transcript	c.1944G>A	p.Gly648Gly	splice_region_variant, synonymous_variant	13/36	ENST00000646693.2	NP_001374212.1
SMARCA4	NM_003072.5 linkuse as main transcript	c.1944G>A	p.Gly648Gly	splice_region_variant, synonymous_variant	13/35	ENST00000344626.10	NP_003063.2	P51532-1A7E2E1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
SMARCA4	ENST00000646693.2 linkuse as main transcript	c.1944G>A	p.Gly648Gly	splice_region_variant, synonymous_variant	13/36		NM_001387283.1	ENSP00000495368.1	Q9HBD4
SMARCA4	ENST00000344626.10 linkuse as main transcript	c.1944G>A	p.Gly648Gly	splice_region_variant, synonymous_variant	13/35	1	NM_003072.5	ENSP00000343896.4	P51532-1
SMARCA4	ENST00000643549.1 linkuse as main transcript	c.1944G>A	p.Gly648Gly	splice_region_variant, synonymous_variant	13/35			ENSP00000493975.1	A0A2R8Y4P4
SMARCA4	ENST00000541122.6 linkuse as main transcript	c.1944G>A	p.Gly648Gly	splice_region_variant, synonymous_variant	14/35	5		ENSP00000445036.2	P51532-4
SMARCA4	ENST00000643296.1 linkuse as main transcript	c.1944G>A	p.Gly648Gly	splice_region_variant, synonymous_variant	13/34			ENSP00000496635.1	P51532-4
SMARCA4	ENST00000644737.1 linkuse as main transcript	c.1944G>A	p.Gly648Gly	splice_region_variant, synonymous_variant	13/34			ENSP00000495548.1	P51532-4
SMARCA4	ENST00000589677.5 linkuse as main transcript	c.1944G>A	p.Gly648Gly	splice_region_variant, synonymous_variant	14/35	5		ENSP00000464778.1	P51532-3
SMARCA4	ENST00000643995.1 linkuse as main transcript	c.1356G>A	p.Gly452Gly	splice_region_variant, synonymous_variant	10/32			ENSP00000496004.1	A0A2R8YGG3
SMARCA4	ENST00000644963.1 linkuse as main transcript	c.588G>A	p.Gly196Gly	splice_region_variant, synonymous_variant	6/28			ENSP00000495599.1	A0A2R8YG32
SMARCA4	ENST00000644065.1 linkuse as main transcript	c.669G>A	p.Gly223Gly	splice_region_variant, synonymous_variant	6/27			ENSP00000493615.1	A0A2R8Y440
SMARCA4	ENST00000642350.1 linkuse as main transcript	c.429G>A	p.Gly143Gly	splice_region_variant, synonymous_variant	5/27			ENSP00000495355.1	A0A2R8Y6N0
SMARCA4	ENST00000643857.1 linkuse as main transcript	c.297G>A	p.Gly99Gly	splice_region_variant, synonymous_variant	4/25			ENSP00000494159.1	A0A2R8Y526

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152194

Hom.:

Cov.:

show subpopulations

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:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461508

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727074

show subpopulations

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:

9.00e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152194

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74358

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000756

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Rhabdoid tumor predisposition syndrome 2

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 10, 2023

- -

Hereditary cancer-predisposing syndrome

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 01, 2016

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

-0.49

CADD

Benign

DANN

Benign

0.51

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00017

dbscSNV1_RF

Benign

0.070

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over