rs757516325

chr19-10991285-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP2 PP3

The NM_001387283.1(SMARCA4):c.1381A>C(p.Lys461Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,458,256 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. K461R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: SMARCA4 NM_001387283.1 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 9.22

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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, SMARCA4
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.765

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SMARCA4	NM_001387283.1	c.1381A>C	p.Lys461Gln	missense_variant	8/36	ENST00000646693.2
SMARCA4	NM_003072.5	c.1381A>C	p.Lys461Gln	missense_variant	8/35	ENST00000344626.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SMARCA4	ENST00000646693.2	c.1381A>C	p.Lys461Gln	missense_variant	8/36		NM_001387283.1
SMARCA4	ENST00000344626.10	c.1381A>C	p.Lys461Gln	missense_variant	8/35	1	NM_003072.5	P4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000416 AC: 1 AN: 240598 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 130462

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000926

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1458256 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 725064

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: 0.00000270

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000825 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

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jan 01, 2022

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 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: "Probably Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 470240). This variant has not been reported in the literature in individuals affected with SMARCA4-related conditions. This variant is present in population databases (rs757516325, gnomAD 0.0009%). This sequence change replaces lysine, which is basic and polar, with glutamine, which is neutral and polar, at codon 461 of the SMARCA4 protein (p.Lys461Gln). -

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 14, 2023

The p.K461Q variant (also known as c.1381A>C), located in coding exon 7 of the SMARCA4 gene, results from an A to C substitution at nucleotide position 1381. The lysine at codon 461 is replaced by glutamine, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. 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). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Benign	0.0080	T
BayesDel_noAF	Benign	-0.23
Cadd	Pathogenic	26
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.77	D;.;T;.;.;.;.;.;.;.;D;.;.;.;.;.;T;T
Eigen	Pathogenic	0.86
Eigen_PC	Pathogenic	0.80
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Uncertain	0.27	D
MetaRNN	Pathogenic	0.76	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.41	T
MutationAssessor	Pathogenic	3.0	M;.;.;.;M;M;.;M;M;M;M;M;M;M;M;M;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D
PrimateAI	Pathogenic	0.90	D
PROVEAN	Uncertain	-3.6	D;.;.;.;.;.;.;.;.;.;D;.;D;.;D;.;D;D
REVEL	Uncertain	0.43
Sift	Uncertain	0.023	D;.;.;.;.;.;.;.;.;.;D;.;D;.;D;.;D;D
Sift4G	Uncertain	0.011	D;.;.;.;.;.;.;.;.;.;D;.;D;D;D;D;D;D
Polyphen		1.0	D;.;D;.;.;.;.;.;.;.;D;.;.;.;.;.;.;D
Vest4		0.62
MutPred		0.48		Gain of ubiquitination at K458 (P = 0.0239);Gain of ubiquitination at K458 (P = 0.0239);Gain of ubiquitination at K458 (P = 0.0239);Gain of ubiquitination at K458 (P = 0.0239);Gain of ubiquitination at K458 (P = 0.0239);Gain of ubiquitination at K458 (P = 0.0239);Gain of ubiquitination at K458 (P = 0.0239);Gain of ubiquitination at K458 (P = 0.0239);Gain of ubiquitination at K458 (P = 0.0239);Gain of ubiquitination at K458 (P = 0.0239);Gain of ubiquitination at K458 (P = 0.0239);Gain of ubiquitination at K458 (P = 0.0239);Gain of ubiquitination at K458 (P = 0.0239);Gain of ubiquitination at K458 (P = 0.0239);Gain of ubiquitination at K458 (P = 0.0239);Gain of ubiquitination at K458 (P = 0.0239);Gain of ubiquitination at K458 (P = 0.0239);Gain of ubiquitination at K458 (P = 0.0239);
MVP		0.71
MPC		2.5
ClinPred		0.97	D
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.88
gMVP		0.99

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: rs757516325; hg19: chr19-11101961;