19-10986922-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP2 BP4

The NM_001387283.1(SMARCA4):c.778A>G(p.Met260Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000186 in 1,612,268 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 Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M260L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: SMARCA4 NM_001387283.1 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 8.38

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, SMARCA4
• BP4: Computational evidence support a benign effect (MetaRNN=0.35234612).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SMARCA4	NM_001387283.1	c.778A>G	p.Met260Val	missense_variant	5/36	ENST00000646693.2
SMARCA4	NM_003072.5	c.778A>G	p.Met260Val	missense_variant	5/35	ENST00000344626.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SMARCA4	ENST00000646693.2	c.778A>G	p.Met260Val	missense_variant	5/36		NM_001387283.1
SMARCA4	ENST00000344626.10	c.778A>G	p.Met260Val	missense_variant	5/35	1	NM_003072.5	P4

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 152016 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1460252 Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2 AN XY: 726518

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: 0.0000166

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 152016 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74256

Gnomad4 AFR AF: 0.0000242

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000756

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

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jan 10, 2022

Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C15"). ClinVar contains an entry for this variant (Variation ID: 484978). This variant has not been reported in the literature in individuals affected with SMARCA4-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces methionine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 260 of the SMARCA4 protein (p.Met260Val). 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. -

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 30, 2023

The p.M260V variant (also known as c.778A>G), located in coding exon 4 of the SMARCA4 gene, results from an A to G substitution at nucleotide position 778. The methionine at codon 260 is replaced by valine, an amino acid with highly similar properties. Missense and in-frame variants in SMARCA4 are known to cause neurodevelopmental disorders; however, such associations with rhabdoid tumor predisposition syndrome including small cell carcinoma of the ovary-hypercalcemic type (SCCOHT) are exceedingly rare (Kosho T et al. Am J Med Genet C Semin Med Genet. 2014 Sep;166C(3):262-75; Jelinic P et al. Nat Genet. 2014 May;46(5):424-6). 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 supporting evidence, the association of this alteration with Coffin-Siris syndrome is unknown; however, the association of this alteration with rhabdoid tumor predisposition syndrome is unlikely. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.060
Cadd	Uncertain	24
Dann	Benign	0.93
DEOGEN2	Benign	0.27	T;.;T;.;.;.;.;.;.;.;T;.;.;.;.;.;T;T
Eigen	Benign	-0.10
Eigen_PC	Benign	0.061
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Uncertain	0.094	D
MetaRNN	Benign	0.35	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.38	T
MutationAssessor	Benign	1.4	L;.;.;.;L;L;.;L;L;L;L;L;L;L;L;L;.;.
MutationTaster	Benign	0.93	D;D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	-0.65	N;.;.;.;.;.;.;.;.;.;N;.;N;.;N;.;N;N
REVEL	Uncertain	0.37
Sift	Benign	0.51	T;.;.;.;.;.;.;.;.;.;T;.;T;.;T;.;T;T
Sift4G	Benign	0.70	T;.;.;.;.;.;.;.;.;.;T;.;T;T;T;T;T;T
Polyphen		0.0	B;.;B;.;.;.;.;.;.;.;B;.;.;.;.;.;.;B
Vest4		0.48
MutPred		0.21		Loss of glycosylation at P261 (P = 0.0999);Loss of glycosylation at P261 (P = 0.0999);Loss of glycosylation at P261 (P = 0.0999);Loss of glycosylation at P261 (P = 0.0999);Loss of glycosylation at P261 (P = 0.0999);Loss of glycosylation at P261 (P = 0.0999);Loss of glycosylation at P261 (P = 0.0999);Loss of glycosylation at P261 (P = 0.0999);Loss of glycosylation at P261 (P = 0.0999);Loss of glycosylation at P261 (P = 0.0999);Loss of glycosylation at P261 (P = 0.0999);Loss of glycosylation at P261 (P = 0.0999);Loss of glycosylation at P261 (P = 0.0999);Loss of glycosylation at P261 (P = 0.0999);Loss of glycosylation at P261 (P = 0.0999);Loss of glycosylation at P261 (P = 0.0999);Loss of glycosylation at P261 (P = 0.0999);Loss of glycosylation at P261 (P = 0.0999);
MVP		0.91
MPC		0.26
ClinPred		0.79	D
GERP RS		4.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.23
gMVP		0.065

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: rs1064795842; hg19: chr19-11097598;