rs772752194

chr19-10996374-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_001387283.1(SMARCA4):c.1755A>T(p.Lys585Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000031 in 1,614,086 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K585E) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: SMARCA4 NM_001387283.1 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:1
• Conservation: PhyloP100: -0.377

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.

• 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=0.07988119).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SMARCA4	NM_001387283.1	c.1755A>T	p.Lys585Asn	missense_variant	10/36	ENST00000646693.2
SMARCA4	NM_003072.5	c.1755A>T	p.Lys585Asn	missense_variant	10/35	ENST00000344626.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SMARCA4	ENST00000646693.2	c.1755A>T	p.Lys585Asn	missense_variant	10/36		NM_001387283.1
SMARCA4	ENST00000344626.10	c.1755A>T	p.Lys585Asn	missense_variant	10/35	1	NM_003072.5	P4

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152224 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000724

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

GnomAD3 exomes AF: 0.0000119 AC: 3 AN: 251186 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135832

Gnomad AFR exome AF: 0.000185

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461862 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 727234

Gnomad4 AFR exome AF: 0.0000597

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 AF: 0.0000197 AC: 3 AN: 152224 Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1 AN XY: 74374

Gnomad4 AFR AF: 0.0000724

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: 0.0000151

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Rhabdoid tumor predisposition syndrome 2 Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Aug 23, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Nov 21, 2023	This sequence change replaces lysine, which is basic and polar, with asparagine, which is neutral and polar, at codon 585 of the SMARCA4 protein (p.Lys585Asn). This variant is present in population databases (rs772752194, gnomAD 0.02%). 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: 470255). 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 with a negative predictive value of 95%. 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. -

Intellectual disability, autosomal dominant 16 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 15, 2021

- -

Hereditary cancer-predisposing syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

May 25, 2023

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.89
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.52
Cadd	Benign	18
Dann	Uncertain	0.99
DEOGEN2	Pathogenic	0.81	D;.;T;.;.;.;.;.;.;.;D;.;.;.;.;.;T;T;.;.;.
Eigen	Benign	-0.44
Eigen_PC	Benign	-0.48
FATHMM_MKL	Benign	0.57	D
M_CAP	Benign	0.0090	T
MetaRNN	Benign	0.080	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Uncertain	2.1	M;.;.;.;M;M;.;M;M;M;M;M;M;M;M;M;.;.;.;.;.
MutationTaster	Benign	0.99	D;D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.71	T
PROVEAN	Benign	-2.3	N;.;.;.;.;.;.;.;.;.;N;.;N;.;N;.;.;N;.;.;.
REVEL	Benign	0.099
Sift	Benign	0.060	T;.;.;.;.;.;.;.;.;.;T;.;D;.;T;.;.;T;.;.;.
Sift4G	Uncertain	0.041	D;.;.;.;.;.;.;.;.;.;D;.;D;T;T;T;T;D;.;.;.
Polyphen		0.29	B;.;B;.;.;.;.;.;.;.;B;.;.;.;.;.;.;B;.;.;.
Vest4		0.32
MutPred		0.27		Gain of loop (P = 0.0045);Gain of loop (P = 0.0045);Gain of loop (P = 0.0045);Gain of loop (P = 0.0045);Gain of loop (P = 0.0045);Gain of loop (P = 0.0045);Gain of loop (P = 0.0045);Gain of loop (P = 0.0045);Gain of loop (P = 0.0045);Gain of loop (P = 0.0045);Gain of loop (P = 0.0045);Gain of loop (P = 0.0045);Gain of loop (P = 0.0045);Gain of loop (P = 0.0045);Gain of loop (P = 0.0045);Gain of loop (P = 0.0045);.;Gain of loop (P = 0.0045);.;.;.;
MVP		0.61
MPC		1.6
ClinPred		0.087	T
GERP RS		-1.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.097
gMVP		0.95

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: rs772752194; hg19: chr19-11107050;