19-10984266-G-T

Position:

• chr19-10984266-G-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.115G>T​(p.Ala39Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,458,738 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: SMARCA4 NM_003072.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.24

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 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). 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.120526075).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SMARCA4	NM_001387283.1	c.115G>T	p.Ala39Ser	missense_variant	2/36	ENST00000646693.2	NP_001374212.1
SMARCA4	NM_003072.5	c.115G>T	p.Ala39Ser	missense_variant	2/35	ENST00000344626.10	NP_003063.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SMARCA4	ENST00000646693.2	c.115G>T	p.Ala39Ser	missense_variant	2/36		NM_001387283.1	ENSP00000495368.1
SMARCA4	ENST00000344626.10	c.115G>T	p.Ala39Ser	missense_variant	2/35	1	NM_003072.5	ENSP00000343896.4
SMARCA4	ENST00000643549.1	c.115G>T	p.Ala39Ser	missense_variant	2/35			ENSP00000493975.1
SMARCA4	ENST00000541122.6	c.115G>T	p.Ala39Ser	missense_variant	3/35	5		ENSP00000445036.2
SMARCA4	ENST00000643296.1	c.115G>T	p.Ala39Ser	missense_variant	2/34			ENSP00000496635.1
SMARCA4	ENST00000644737.1	c.115G>T	p.Ala39Ser	missense_variant	2/34			ENSP00000495548.1
SMARCA4	ENST00000589677.5	c.115G>T	p.Ala39Ser	missense_variant	3/35	5		ENSP00000464778.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000838 AC: 2 AN: 238588 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 130550

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000111

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: 0.00000274 AC: 4 AN: 1458738 Hom.: 0 Cov.: 33 AF XY: 0.00000276 AC XY: 2 AN XY: 725546

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.0000165 AC: 2

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

Sep 10, 2022

This sequence change replaces alanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 39 of the SMARCA4 protein (p.Ala39Ser). This variant is present in population databases (rs764312409, 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: 408670). 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	Benign	0.062
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	21
DANN	Benign	0.97
DEOGEN2	Benign	0.22	T;.;T;.;.;.;.;.;.;.;T;.;.;.;.;.;.;T;T
Eigen	Benign	-0.64
Eigen_PC	Benign	-0.47
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Benign	0.77	.;T;.;.;.;.;T;.;.;.;T;T;.;T;T;T;T;T;T
M_CAP	Uncertain	0.23	D
MetaRNN	Benign	0.12	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.49	T
MutationAssessor	Benign	0.0	N;.;.;.;N;N;.;N;N;N;N;.;N;N;N;N;N;.;.
PrimateAI	Uncertain	0.72	T
PROVEAN	Benign	-0.37	N;.;.;.;.;.;.;.;.;.;N;.;.;N;.;N;.;N;N
REVEL	Benign	0.21
Sift	Benign	0.16	T;.;.;.;.;.;.;.;.;.;T;.;.;T;.;T;.;T;T
Sift4G	Benign	0.54	T;.;.;.;.;.;.;.;.;.;T;.;.;T;T;T;T;T;T
Polyphen		0.0070	B;.;B;.;.;.;.;.;.;.;B;.;.;.;.;.;.;.;B
Vest4		0.16
MutPred		0.15		Gain of phosphorylation at A39 (P = 0.0022);Gain of phosphorylation at A39 (P = 0.0022);Gain of phosphorylation at A39 (P = 0.0022);Gain of phosphorylation at A39 (P = 0.0022);Gain of phosphorylation at A39 (P = 0.0022);Gain of phosphorylation at A39 (P = 0.0022);Gain of phosphorylation at A39 (P = 0.0022);Gain of phosphorylation at A39 (P = 0.0022);Gain of phosphorylation at A39 (P = 0.0022);Gain of phosphorylation at A39 (P = 0.0022);Gain of phosphorylation at A39 (P = 0.0022);Gain of phosphorylation at A39 (P = 0.0022);Gain of phosphorylation at A39 (P = 0.0022);Gain of phosphorylation at A39 (P = 0.0022);Gain of phosphorylation at A39 (P = 0.0022);Gain of phosphorylation at A39 (P = 0.0022);Gain of phosphorylation at A39 (P = 0.0022);Gain of phosphorylation at A39 (P = 0.0022);Gain of phosphorylation at A39 (P = 0.0022);
MVP		0.47
MPC		0.23
ClinPred		0.075	T
GERP RS		3.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.030
gMVP		0.047

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs764312409; hg19: chr19-11094942;