chr19-11034176-C-G

Position:

• chr19-11034176-C-G

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.3927C>G​(p.His1309Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: SMARCA4 NM_003072.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -2.99

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 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). The gene has 59 curated pathogenic missense variants (we use a threshold of 10). The gene has 56 curated benign missense variants. GenCC has associacion of the 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.09542781).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SMARCA4	NM_001387283.1	c.3927C>G	p.His1309Gln	missense_variant	28/36	ENST00000646693.2	NP_001374212.1
SMARCA4	NM_003072.5	c.3927C>G	p.His1309Gln	missense_variant	28/35	ENST00000344626.10	NP_003063.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SMARCA4	ENST00000646693.2	c.3927C>G	p.His1309Gln	missense_variant	28/36		NM_001387283.1	ENSP00000495368.1
SMARCA4	ENST00000344626.10	c.3927C>G	p.His1309Gln	missense_variant	28/35	1	NM_003072.5	ENSP00000343896.4
SMARCA4	ENST00000643549.1	c.3828C>G	p.His1276Gln	missense_variant	27/35			ENSP00000493975.1
SMARCA4	ENST00000541122.6	c.3828C>G	p.His1276Gln	missense_variant	28/35	5		ENSP00000445036.2
SMARCA4	ENST00000643296.1	c.3828C>G	p.His1276Gln	missense_variant	27/34			ENSP00000496635.1
SMARCA4	ENST00000644737.1	c.3828C>G	p.His1276Gln	missense_variant	27/34			ENSP00000495548.1
SMARCA4	ENST00000589677.5	c.3828C>G	p.His1276Gln	missense_variant	28/35	5		ENSP00000464778.1
SMARCA4	ENST00000643995.1	c.3339C>G	p.His1113Gln	missense_variant	25/32			ENSP00000496004.1
SMARCA4	ENST00000644963.1	c.2571C>G	p.His857Gln	missense_variant	21/28			ENSP00000495599.1
SMARCA4	ENST00000644065.1	c.2553C>G	p.His851Gln	missense_variant	20/27			ENSP00000493615.1
SMARCA4	ENST00000642350.1	c.2412C>G	p.His804Gln	missense_variant	20/27			ENSP00000495355.1
SMARCA4	ENST00000643857.1	c.2280C>G	p.His760Gln	missense_variant	19/25			ENSP00000494159.1
SMARCA4	ENST00000538456.4	c.84C>G	p.His28Gln	missense_variant	2/8	3		ENSP00000495197.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Rhabdoid tumor predisposition syndrome 2 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 03, 2023

This sequence change replaces histidine, which is basic and polar, with glutamine, which is neutral and polar, at codon 1309 of the SMARCA4 protein (p.His1309Gln). 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: 1040320). 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. 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.34
BayesDel_addAF	Benign	-0.072	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	2.7
DANN	Benign	0.93
DEOGEN2	Benign	0.23	T;.;T;.;.;.;.;.;.;.;T;.;.;.;.;.;T;T;.;.;.;.
Eigen	Benign	-0.92
Eigen_PC	Benign	-0.96
FATHMM_MKL	Benign	0.36	N
LIST_S2	Benign	0.78	.;T;.;.;.;.;T;.;.;.;T;.;T;T;T;T;T;T;T;T;T;T
M_CAP	Benign	0.064	D
MetaRNN	Benign	0.095	T;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	0.55	N;.;.;.;.;.;.;.;.;.;N;.;.;.;.;.;.;.;.;.;.;.
PrimateAI	Pathogenic	0.81	D
PROVEAN	Benign	-0.33	N;.;.;.;.;.;.;.;.;.;N;.;N;.;N;.;N;.;.;.;.;.
REVEL	Benign	0.26
Sift	Uncertain	0.022	D;.;.;.;.;.;.;.;.;.;D;.;D;.;D;.;T;.;.;.;.;.
Sift4G	Uncertain	0.020	D;.;.;.;.;.;.;.;.;.;D;.;D;D;D;D;D;D;.;.;.;.
Polyphen		0.089	B;.;B;.;.;.;.;.;.;.;B;.;.;.;.;.;.;B;.;.;.;.
Vest4		0.30
MutPred		0.32		Loss of helix (P = 0.1299);.;Loss of helix (P = 0.1299);.;.;.;.;.;.;.;Loss of helix (P = 0.1299);.;.;.;.;.;.;Loss of helix (P = 0.1299);.;.;.;.;
MVP		0.54
MPC		1.7
ClinPred		0.64	D
GERP RS		-1.3
Varity_R		0.12
gMVP		0.83

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: rs148495641; hg19: chr19-11144852;