19-11003131-C-G

Position:

• chr19-11003131-C-G

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PP2 BS2

The NM_003072.5(SMARCA4):​c.1915C>G​(p.Leu639Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000682 in 1,614,046 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: SMARCA4 NM_003072.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:1 O:1
• Conservation: PhyloP100: 1.40

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 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -3 ACMG points.

• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), SMARCA4. . Gene score misZ 6.8459 (greater than the threshold 3.09). Trascript score misZ 8.7957 (greater than threshold 3.09). GenCC has associacion of gene with uterine corpus sarcoma, Coffin-Siris syndrome 1, intellectual disability, autosomal dominant 16, rhabdoid tumor predisposition syndrome 2, familial rhabdoid tumor, hereditary nonpolyposis colon cancer, Coffin-Siris syndrome.
• BS2: High AC in GnomAdExome4 at 8 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SMARCA4	NM_001387283.1	c.1915C>G	p.Leu639Val	missense_variant	12/36	ENST00000646693.2	NP_001374212.1
SMARCA4	NM_003072.5	c.1915C>G	p.Leu639Val	missense_variant	12/35	ENST00000344626.10	NP_003063.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SMARCA4	ENST00000646693.2	c.1915C>G	p.Leu639Val	missense_variant	12/36		NM_001387283.1	ENSP00000495368.1
SMARCA4	ENST00000344626.10	c.1915C>G	p.Leu639Val	missense_variant	12/35	1	NM_003072.5	ENSP00000343896.4
SMARCA4	ENST00000643549.1	c.1915C>G	p.Leu639Val	missense_variant	12/35			ENSP00000493975.1
SMARCA4	ENST00000541122.6	c.1915C>G	p.Leu639Val	missense_variant	13/35	5		ENSP00000445036.2
SMARCA4	ENST00000643296.1	c.1915C>G	p.Leu639Val	missense_variant	12/34			ENSP00000496635.1
SMARCA4	ENST00000644737.1	c.1915C>G	p.Leu639Val	missense_variant	12/34			ENSP00000495548.1
SMARCA4	ENST00000589677.5	c.1915C>G	p.Leu639Val	missense_variant	13/35	5		ENSP00000464778.1
SMARCA4	ENST00000643995.1	c.1327C>G	p.Leu443Val	missense_variant	9/32			ENSP00000496004.1
SMARCA4	ENST00000644963.1	c.559C>G	p.Leu187Val	missense_variant	5/28			ENSP00000495599.1
SMARCA4	ENST00000644065.1	c.640C>G	p.Leu214Val	missense_variant	5/27			ENSP00000493615.1
SMARCA4	ENST00000642350.1	c.400C>G	p.Leu134Val	missense_variant	4/27			ENSP00000495355.1
SMARCA4	ENST00000643857.1	c.268C>G	p.Leu90Val	missense_variant	3/25			ENSP00000494159.1

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152194 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

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

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251296 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135872

Gnomad AFR exome AF: 0.0000617

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000547 AC: 8 AN: 1461852 Hom.: 0 Cov.: 33 AF XY: 0.00000413 AC XY: 3 AN XY: 727228

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: 0.00000719

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152194 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74352

Gnomad4 AFR AF: 0.0000241

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: 0.0000151

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:1 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Rhabdoid tumor predisposition syndrome 2 Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 27, 2023	This sequence change replaces leucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 639 of the SMARCA4 protein (p.Leu639Val). This variant is present in population databases (rs587778680, gnomAD 0.007%). 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: 135247). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on SMARCA4 protein function. 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	May 08, 2023	- -

Intellectual disability, autosomal dominant 16 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 15, 2021

- -

Hereditary cancer-predisposing syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 05, 2024

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. -

not specified Other:1

not provided, no classification provided

reference population

ITMI

Sep 19, 2013

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.60
BayesDel_addAF	Benign	-0.053	T
BayesDel_noAF	Benign	-0.13
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.23	T;.;T;.;.;.;.;.;.;.;T;.;.;.;.;.;T;T;.;.;.;.
Eigen	Benign	0.17
Eigen_PC	Benign	0.13
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Pathogenic	0.98	.;D;.;.;.;.;D;.;.;.;D;.;D;D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.38	D
MetaRNN	Uncertain	0.68	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	-0.13	T
MutationAssessor	Benign	1.6	L;.;.;.;L;L;.;L;L;L;L;L;L;L;L;L;.;.;.;.;.;.
PrimateAI	Uncertain	0.76	T
PROVEAN	Benign	-1.7	N;.;.;.;.;.;.;.;.;.;N;.;N;.;N;.;.;N;.;.;.;.
REVEL	Uncertain	0.58
Sift	Benign	0.16	T;.;.;.;.;.;.;.;.;.;T;.;T;.;T;.;.;T;.;.;.;.
Sift4G	Benign	0.23	T;.;.;.;.;.;.;.;.;.;T;.;T;T;T;T;T;T;.;.;.;.
Polyphen		0.88	P;.;P;.;.;.;.;.;.;.;P;.;.;.;.;.;.;P;.;.;.;.
Vest4		0.72
MutPred		0.61		Loss of helix (P = 0.028);Loss of helix (P = 0.028);Loss of helix (P = 0.028);Loss of helix (P = 0.028);Loss of helix (P = 0.028);Loss of helix (P = 0.028);Loss of helix (P = 0.028);Loss of helix (P = 0.028);Loss of helix (P = 0.028);Loss of helix (P = 0.028);Loss of helix (P = 0.028);Loss of helix (P = 0.028);Loss of helix (P = 0.028);Loss of helix (P = 0.028);Loss of helix (P = 0.028);Loss of helix (P = 0.028);.;Loss of helix (P = 0.028);.;.;.;.;
MVP		0.74
MPC		2.5
ClinPred		0.64	D
GERP RS		1.3
RBP_binding_hub_radar		1.0
RBP_regulation_power_radar		3.9
Varity_R		0.16
gMVP		0.82

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

Publications

LitVar

Other links and lift over

dbSNP: rs587778680; hg19: chr19-11113807;