19-10987693-C-T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 1P and 6B. PP2 BP4_Moderate BS2

The NM_001387283.1(SMARCA4):c.887C>T(p.Thr296Met) variant causes a missense change. The variant allele was found at a frequency of 0.0000116 in 1,460,492 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). Synonymous variant affecting the same amino acid position (i.e. T296T) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: SMARCA4 NM_001387283.1 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:1
• Conservation: PhyloP100: 5.37

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 Likely_benign. Variant got -5 ACMG points.

• PP2: Missense variant where missense usually causes diseases, SMARCA4
• BP4: Computational evidence support a benign effect (MetaRNN=0.26314324).
• BS2: High AC in GnomAdExome at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SMARCA4	NM_001387283.1	c.887C>T	p.Thr296Met	missense_variant	6/36	ENST00000646693.2
SMARCA4	NM_003072.5	c.887C>T	p.Thr296Met	missense_variant	6/35	ENST00000344626.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SMARCA4	ENST00000646693.2	c.887C>T	p.Thr296Met	missense_variant	6/36		NM_001387283.1
SMARCA4	ENST00000344626.10	c.887C>T	p.Thr296Met	missense_variant	6/35	1	NM_003072.5	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000207 AC: 5 AN: 241264 Hom.: 0 AF XY: 0.0000228 AC XY: 3 AN XY: 131740

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000551

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000284

Gnomad OTH exome AF: 0.000168

GnomAD4 exome AF: 0.0000116 AC: 17 AN: 1460492 Hom.: 0 Cov.: 33 AF XY: 0.0000179 AC XY: 13 AN XY: 726576

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000117

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.0000248 AC: 3

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Mar 23, 2023	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. -
Uncertain significance, criteria provided, single submitter	curation	Sema4, Sema4	Aug 26, 2021	- -

Intellectual disability, autosomal dominant 16 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 15, 2021

- -

Rhabdoid tumor predisposition syndrome 2 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jan 06, 2024

This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 296 of the SMARCA4 protein (p.Thr296Met). This variant is present in population databases (rs781066262, gnomAD 0.006%). 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: 238526). 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) performed at Invitae indicates that this missense variant is not expected to disrupt SMARCA4 protein function with a negative predictive value of 95%. 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. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Jan 27, 2023

In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 35432459) -

SMARCA4-related disorder Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 07, 2023

The SMARCA4 c.887C>T variant is predicted to result in the amino acid substitution p.Thr296Met. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0055% of alleles in individuals of East Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/19-11098369-C-T). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.25
Cadd	Uncertain	26
Dann	Uncertain	0.99
DEOGEN2	Benign	0.30	T;.;T;.;.;.;.;.;.;.;T;.;.;.;.;.;T;T
Eigen	Benign	0.065
Eigen_PC	Benign	0.13
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Uncertain	0.18	D
MetaRNN	Benign	0.26	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.084	D
MutationAssessor	Benign	0.69	N;.;.;.;N;N;.;N;N;N;N;N;N;N;N;N;.;.
MutationTaster	Benign	0.71	D;D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-1.0	N;.;.;.;.;.;.;.;.;.;N;.;N;.;N;.;N;N
REVEL	Uncertain	0.31
Sift	Uncertain	0.014	D;.;.;.;.;.;.;.;.;.;D;.;D;.;D;.;D;D
Sift4G	Benign	0.12	T;.;.;.;.;.;.;.;.;.;T;.;T;T;T;T;T;T
Polyphen		0.95	P;.;D;.;.;.;.;.;.;.;P;.;.;.;.;.;.;D
Vest4		0.44
MutPred		0.20		Loss of glycosylation at T296 (P = 0.0022);Loss of glycosylation at T296 (P = 0.0022);Loss of glycosylation at T296 (P = 0.0022);Loss of glycosylation at T296 (P = 0.0022);Loss of glycosylation at T296 (P = 0.0022);Loss of glycosylation at T296 (P = 0.0022);Loss of glycosylation at T296 (P = 0.0022);Loss of glycosylation at T296 (P = 0.0022);Loss of glycosylation at T296 (P = 0.0022);Loss of glycosylation at T296 (P = 0.0022);Loss of glycosylation at T296 (P = 0.0022);Loss of glycosylation at T296 (P = 0.0022);Loss of glycosylation at T296 (P = 0.0022);Loss of glycosylation at T296 (P = 0.0022);Loss of glycosylation at T296 (P = 0.0022);Loss of glycosylation at T296 (P = 0.0022);Loss of glycosylation at T296 (P = 0.0022);Loss of glycosylation at T296 (P = 0.0022);
MVP		0.59
MPC		0.58
ClinPred		0.39	T
GERP RS		4.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.3
Varity_R		0.050
gMVP		0.028

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: rs781066262; hg19: chr19-11098369;