rs1060502105

chr19-11007902-G-Achr19-11007902-G-Cchr19-11007902-G-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 1P and 3B. PP2 BP4_Moderate BP6

The NM_001387283.1(SMARCA4):c.2002G>A(p.Glu668Lys) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000754 in 1,458,794 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. 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. E668Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000075 (0 hom.)
• Consequence: SMARCA4 NM_001387283.1 missense, splice_region
• Scores: Splicing: ADA: 0.9260
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: 7.37

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 Likely_benign. Variant got -2 ACMG points.

• PP2: Missense variant where missense usually causes diseases, SMARCA4
• BP4: Computational evidence support a benign effect (MetaRNN=0.21963206).
• BP6: Variant 19-11007902-G-A is Benign according to our data. Variant chr19-11007902-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 408715.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Likely_benign=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SMARCA4	NM_001387283.1	c.2002G>A	p.Glu668Lys	missense_variant, splice_region_variant	14/36	ENST00000646693.2
SMARCA4	NM_003072.5	c.2002G>A	p.Glu668Lys	missense_variant, splice_region_variant	14/35	ENST00000344626.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SMARCA4	ENST00000646693.2	c.2002G>A	p.Glu668Lys	missense_variant, splice_region_variant	14/36		NM_001387283.1
SMARCA4	ENST00000344626.10	c.2002G>A	p.Glu668Lys	missense_variant, splice_region_variant	14/35	1	NM_003072.5	P4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.00000399 AC: 1 AN: 250682 Hom.: 0 AF XY: 0.00000738 AC XY: 1 AN XY: 135546

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: 0.00000882

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000754 AC: 11 AN: 1458794 Hom.: 0 Cov.: 31 AF XY: 0.0000124 AC XY: 9 AN XY: 725708

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000811

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

Alfa AF: 0.000111 Hom.: 0

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Intellectual disability, autosomal dominant 16 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 15, 2021

- -

Rhabdoid tumor predisposition syndrome 2 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Sep 27, 2023

This variant is present in population databases (no rsID available, gnomAD 0.0009%). 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. Studies have shown that this missense change is associated with altered splicing resulting in unknown protein product impact (Invitae). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. ClinVar contains an entry for this variant (Variation ID: 408715). This variant has not been reported in the literature in individuals affected with SMARCA4-related conditions. This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 668 of the SMARCA4 protein (p.Glu668Lys). -

Hereditary cancer-predisposing syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 21, 2024

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	Uncertain	0.43
BayesDel_addAF	Benign	-0.086	T
BayesDel_noAF	Benign	-0.36
Cadd	Pathogenic	35
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.50	T;.;T;.;.;.;.;.;.;.;T;.;.;.;.;.;T;T;.;.;.
Eigen	Benign	0.075
Eigen_PC	Benign	0.21
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Benign	0.022	T
MetaRNN	Benign	0.22	T;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	1.5	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	Uncertain	0.64	T
PROVEAN	Benign	-2.1	N;.;.;.;.;.;.;.;.;.;N;.;N;.;N;.;.;N;.;.;.
REVEL	Benign	0.060
Sift	Benign	0.096	T;.;.;.;.;.;.;.;.;.;T;.;T;.;T;.;.;T;.;.;.
Sift4G	Benign	0.13	T;.;.;.;.;.;.;.;.;.;T;.;T;T;T;T;T;T;.;.;.
Polyphen		0.0010	B;.;B;.;.;.;.;.;.;.;B;.;.;.;.;.;.;B;.;.;.
Vest4		0.56
MutPred		0.31		Gain of glycosylation at E668 (P = 0.0122);Gain of glycosylation at E668 (P = 0.0122);Gain of glycosylation at E668 (P = 0.0122);Gain of glycosylation at E668 (P = 0.0122);Gain of glycosylation at E668 (P = 0.0122);Gain of glycosylation at E668 (P = 0.0122);Gain of glycosylation at E668 (P = 0.0122);Gain of glycosylation at E668 (P = 0.0122);Gain of glycosylation at E668 (P = 0.0122);Gain of glycosylation at E668 (P = 0.0122);Gain of glycosylation at E668 (P = 0.0122);Gain of glycosylation at E668 (P = 0.0122);Gain of glycosylation at E668 (P = 0.0122);Gain of glycosylation at E668 (P = 0.0122);Gain of glycosylation at E668 (P = 0.0122);Gain of glycosylation at E668 (P = 0.0122);.;Gain of glycosylation at E668 (P = 0.0122);.;.;.;
MVP		0.49
MPC		1.4
ClinPred		0.66	D
GERP RS		4.3
Varity_R		0.16
gMVP		0.73

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.93
dbscSNV1_RF	Benign	0.59
SpliceAI score (max)		0.68		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.68		Position offset: 3

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1060502105; hg19: chr19-11118578;