rs1555762188

chr19-10994991-G-Achr19-10994991-G-Cchr19-10994991-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 1P and 0B. PP2

The NM_001387283.1(SMARCA4):c.1583G>A(p.Arg528Gln) variant causes a missense change involving the alteration of a conserved nucleotide. 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. R528W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: SMARCA4 NM_001387283.1 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 9.97

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.

• PP2: Missense variant where missense usually causes diseases, SMARCA4

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SMARCA4	NM_001387283.1	c.1583G>A	p.Arg528Gln	missense_variant	9/36	ENST00000646693.2
SMARCA4	NM_003072.5	c.1583G>A	p.Arg528Gln	missense_variant	9/35	ENST00000344626.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SMARCA4	ENST00000646693.2	c.1583G>A	p.Arg528Gln	missense_variant	9/36		NM_001387283.1
SMARCA4	ENST00000344626.10	c.1583G>A	p.Arg528Gln	missense_variant	9/35	1	NM_003072.5	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1459460 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 725806

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

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

May 07, 2021

In summary, this variant is a novel missense change with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C35"). This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a SMARCA4-related disease. This sequence change replaces arginine with glutamine at codon 528 of the SMARCA4 protein (p.Arg528Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine. -

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 09, 2022

The p.R528Q variant (also known as c.1583G>A), located in coding exon 8 of the SMARCA4 gene, results from a G to A substitution at nucleotide position 1583. The arginine at codon 528 is replaced by glutamine, an amino acid with highly 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). 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	Pathogenic	0.98
BayesDel_addAF	Benign	-0.031	T
BayesDel_noAF	Benign	-0.28
Cadd	Pathogenic	29
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.70	D;.;T;.;.;.;.;.;.;.;D;.;.;.;.;.;T;T;.;.
Eigen	Uncertain	0.47
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Benign	0.044	D
MetaRNN	Uncertain	0.50	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.3	L;.;.;.;L;L;.;L;L;L;L;L;L;L;L;L;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D
PrimateAI	Pathogenic	0.89	D
PROVEAN	Uncertain	-2.8	D;.;.;.;.;.;.;.;.;.;D;.;D;.;D;.;D;D;.;.
REVEL	Benign	0.16
Sift	Benign	0.74	T;.;.;.;.;.;.;.;.;.;T;.;T;.;T;.;T;T;.;.
Sift4G	Benign	0.66	T;.;.;.;.;.;.;.;.;.;T;.;T;T;T;T;T;T;.;.
Polyphen		0.94	P;.;P;.;.;.;.;.;.;.;P;.;.;.;.;.;.;P;.;.
Vest4		0.54
MutPred		0.47		Loss of MoRF binding (P = 0.0285);Loss of MoRF binding (P = 0.0285);Loss of MoRF binding (P = 0.0285);Loss of MoRF binding (P = 0.0285);Loss of MoRF binding (P = 0.0285);Loss of MoRF binding (P = 0.0285);Loss of MoRF binding (P = 0.0285);Loss of MoRF binding (P = 0.0285);Loss of MoRF binding (P = 0.0285);Loss of MoRF binding (P = 0.0285);Loss of MoRF binding (P = 0.0285);Loss of MoRF binding (P = 0.0285);Loss of MoRF binding (P = 0.0285);Loss of MoRF binding (P = 0.0285);Loss of MoRF binding (P = 0.0285);Loss of MoRF binding (P = 0.0285);Loss of MoRF binding (P = 0.0285);Loss of MoRF binding (P = 0.0285);.;.;
MVP		0.65
MPC		1.9
ClinPred		0.98	D
GERP RS		4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.31
gMVP		0.97

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: rs1555762188; hg19: chr19-11105667; COSMIC: COSV60792110; COSMIC: COSV60792110;