19-11003108-C-T

Variant names:

• chr19-11003108-C-T
• rs1555768365
• NM_001387283.1:c.1892C>T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_003072.5(SMARCA4):​c.1892C>T​(p.Thr631Ile) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict 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. T631T) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SMARCA4 NM_003072.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:1
• Conservation: PhyloP100: 4.59

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 Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the SMARCA4 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 59 curated pathogenic missense variants (we use a threshold of 10). The gene has 56 curated benign missense variants. Gene score misZ: 6.8459 (above the threshold of 3.09). Trascript score misZ: 8.7957 (above the threshold of 3.09). GenCC associations: The gene is linked to 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.15460283).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMARCA4	NM_001387283.1	c.1892C>T	p.Thr631Ile	missense_variant	Exon 12 of 36	ENST00000646693.2	NP_001374212.1
SMARCA4	NM_003072.5	c.1892C>T	p.Thr631Ile	missense_variant	Exon 12 of 35	ENST00000344626.10	NP_003063.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMARCA4	ENST00000646693.2	c.1892C>T	p.Thr631Ile	missense_variant	Exon 12 of 36		NM_001387283.1	ENSP00000495368.1
SMARCA4	ENST00000344626.10	c.1892C>T	p.Thr631Ile	missense_variant	Exon 12 of 35	1	NM_003072.5	ENSP00000343896.4
SMARCA4	ENST00000643549.1	c.1892C>T	p.Thr631Ile	missense_variant	Exon 12 of 35			ENSP00000493975.1
SMARCA4	ENST00000541122.6	c.1892C>T	p.Thr631Ile	missense_variant	Exon 13 of 35	5		ENSP00000445036.2
SMARCA4	ENST00000643296.1	c.1892C>T	p.Thr631Ile	missense_variant	Exon 12 of 34			ENSP00000496635.1
SMARCA4	ENST00000644737.1	c.1892C>T	p.Thr631Ile	missense_variant	Exon 12 of 34			ENSP00000495548.1
SMARCA4	ENST00000589677.5	c.1892C>T	p.Thr631Ile	missense_variant	Exon 13 of 35	5		ENSP00000464778.1
SMARCA4	ENST00000643995.1	c.1304C>T	p.Thr435Ile	missense_variant	Exon 9 of 32			ENSP00000496004.1
SMARCA4	ENST00000644963.1	c.536C>T	p.Thr179Ile	missense_variant	Exon 5 of 28			ENSP00000495599.1
SMARCA4	ENST00000644065.1	c.617C>T	p.Thr206Ile	missense_variant	Exon 5 of 27			ENSP00000493615.1
SMARCA4	ENST00000642350.1	c.377C>T	p.Thr126Ile	missense_variant	Exon 4 of 27			ENSP00000495355.1
SMARCA4	ENST00000643857.1	c.245C>T	p.Thr82Ile	missense_variant	Exon 3 of 25			ENSP00000494159.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Rhabdoid tumor predisposition syndrome 2 Uncertain:2

May 26, 2023

Baylor Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 24, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 631 of the SMARCA4 protein (p.Thr631Ile). This variant is not present in population databases (gnomAD no frequency). 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: 480596). 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. -

Intellectual disability, autosomal dominant 16 Uncertain:1

Jul 15, 2021

Genome-Nilou Lab

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

SMARCA4-related disorder Uncertain:1

Mar 19, 2023

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The SMARCA4 c.1892C>T variant is predicted to result in the amino acid substitution p.Thr631Ile. To our knowledge, this variant has not been reported in the literature or in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. It is interpreted as uncertain significance in ClinVar (https://preview.ncbi.nlm.nih.gov/clinvar/variation/480596/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Hereditary cancer-predisposing syndrome Benign:1

Feb 19, 2024

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
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.48
CADD	Uncertain	24
DANN	Benign	0.96
DEOGEN2	Benign	0.25	T;.;T;.;.;.;.;.;.;.;T;.;.;.;.;.;T;T;.;.;.
Eigen	Benign	-0.17
Eigen_PC	Benign	0.0061
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.90	.;D;.;.;.;.;D;.;.;.;D;.;D;D;D;D;D;D;D;D;D
M_CAP	Benign	0.0068	T
MetaRNN	Benign	0.15	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.90	L;.;.;.;L;L;.;L;L;L;L;L;L;L;L;L;.;.;.;.;.
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-1.8	N;.;.;.;.;.;.;.;.;.;N;.;N;.;N;.;.;N;.;.;.
REVEL	Benign	0.043
Sift	Benign	0.22	T;.;.;.;.;.;.;.;.;.;T;.;T;.;T;.;.;T;.;.;.
Sift4G	Benign	0.45	T;.;.;.;.;.;.;.;.;.;T;.;T;T;T;T;T;T;.;.;.
Polyphen		0.0010	B;.;B;.;.;.;.;.;.;.;B;.;.;.;.;.;.;B;.;.;.
Vest4		0.24
MutPred		0.45		Loss of sheet (P = 0.0228);Loss of sheet (P = 0.0228);Loss of sheet (P = 0.0228);Loss of sheet (P = 0.0228);Loss of sheet (P = 0.0228);Loss of sheet (P = 0.0228);Loss of sheet (P = 0.0228);Loss of sheet (P = 0.0228);Loss of sheet (P = 0.0228);Loss of sheet (P = 0.0228);Loss of sheet (P = 0.0228);Loss of sheet (P = 0.0228);Loss of sheet (P = 0.0228);Loss of sheet (P = 0.0228);Loss of sheet (P = 0.0228);Loss of sheet (P = 0.0228);.;Loss of sheet (P = 0.0228);.;.;.;
MVP		0.39
MPC		1.3
ClinPred		0.34	T
GERP RS		4.6
RBP_binding_hub_radar		1.1
RBP_regulation_power_radar		2.8
Varity_R		0.075
gMVP		0.41

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: rs1555768365; hg19: chr19-11113784;