19-10984278-A-G

Variant names:

• chr19-10984278-A-G
• rs375812959
• NM_001387283.1:c.127A>G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP2

The NM_003072.5(SMARCA4):​c.127A>G​(p.Met43Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000686 in 1,458,514 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: SMARCA4 NM_003072.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 7.46

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 3 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMARCA4	NM_001387283.1	c.127A>G	p.Met43Val	missense_variant	Exon 2 of 36	ENST00000646693.2	NP_001374212.1
SMARCA4	NM_003072.5	c.127A>G	p.Met43Val	missense_variant	Exon 2 of 35	ENST00000344626.10	NP_003063.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMARCA4	ENST00000646693.2	c.127A>G	p.Met43Val	missense_variant	Exon 2 of 36		NM_001387283.1	ENSP00000495368.1
SMARCA4	ENST00000344626.10	c.127A>G	p.Met43Val	missense_variant	Exon 2 of 35	1	NM_003072.5	ENSP00000343896.4
SMARCA4	ENST00000643549.1	c.127A>G	p.Met43Val	missense_variant	Exon 2 of 35			ENSP00000493975.1
SMARCA4	ENST00000541122.6	c.127A>G	p.Met43Val	missense_variant	Exon 3 of 35	5		ENSP00000445036.2
SMARCA4	ENST00000643296.1	c.127A>G	p.Met43Val	missense_variant	Exon 2 of 34			ENSP00000496635.1
SMARCA4	ENST00000644737.1	c.127A>G	p.Met43Val	missense_variant	Exon 2 of 34			ENSP00000495548.1
SMARCA4	ENST00000589677.5	c.127A>G	p.Met43Val	missense_variant	Exon 3 of 35	5		ENSP00000464778.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.86e-7 AC: 1 AN: 1458514 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 725416

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: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Rhabdoid tumor predisposition syndrome 2 Uncertain:1

Nov 16, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. This variant has not been reported in the literature in individuals with SMARCA4-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change replaces methionine with valine at codon 43 of the SMARCA4 protein (p.Met43Val). The methionine residue is highly conserved and there is a small physicochemical difference between methionine and valine. -

Hereditary cancer-predisposing syndrome Uncertain:1

Mar 21, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.M43V variant (also known as c.127A>G), located in coding exon 1 of the SMARCA4 gene, results from an A to G substitution at nucleotide position 127. The methionine at codon 43 is replaced by valine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.27
BayesDel_addAF	Uncertain	0.085	D
BayesDel_noAF	Benign	-0.12
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.43	T;.;T;.;.;.;.;.;.;.;T;.;.;.;.;.;.;T;T
Eigen	Benign	0.00078
Eigen_PC	Benign	0.13
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.87	.;D;.;.;.;.;D;.;.;.;D;D;.;D;D;D;D;D;D
M_CAP	Uncertain	0.25	D
MetaRNN	Uncertain	0.44	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	-0.19	T
MutationAssessor	Benign	1.1	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;N
REVEL	Uncertain	0.37
Sift	Pathogenic	0.0	D;.;.;.;.;.;.;.;.;.;D;.;.;D;.;D;.;D;D
Sift4G	Benign	0.15	T;.;.;.;.;.;.;.;.;.;T;.;.;T;T;T;T;T;T
Polyphen		0.0010	B;.;B;.;.;.;.;.;.;.;B;.;.;.;.;.;.;.;B
Vest4		0.69
MVP		0.77
MPC		0.26
ClinPred		0.93	D
GERP RS		3.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.74
gMVP		0.35

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: rs375812959; hg19: chr19-11094954;