19-10985405-G-C

Position:

• chr19-10985405-G-C

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2 PP2 PP3_Strong

The NM_001387283.1(SMARCA4):​c.355G>C​(p.Gly119Arg) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 3/3 splice prediction tools predicting alterations to normal splicing. 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. G119D) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SMARCA4 NM_001387283.1 missense, splice_region
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.88

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_pathogenic. Variant got 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, SMARCA4
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SMARCA4	NM_001387283.1	c.355G>C	p.Gly119Arg	missense_variant, splice_region_variant	3/36	ENST00000646693.2
SMARCA4	NM_003072.5	c.355G>C	p.Gly119Arg	missense_variant, splice_region_variant	3/35	ENST00000344626.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SMARCA4	ENST00000646693.2	c.355G>C	p.Gly119Arg	missense_variant, splice_region_variant	3/36		NM_001387283.1
SMARCA4	ENST00000344626.10	c.355G>C	p.Gly119Arg	missense_variant, splice_region_variant	3/35	1	NM_003072.5	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Rhabdoid tumor predisposition syndrome 2 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Dec 12, 2017

Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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. Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. This variant has not been reported in the literature in individuals with SMARCA4-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change replaces glycine with arginine at codon 119 of the SMARCA4 protein (p.Gly119Arg). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and arginine. This variant also falls at the last nucleotide of exon 3 of the SMARCA4 coding sequence, which is part of the consensus splice site for this exon. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.28
CADD	Pathogenic	34
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.80	D;.;T;.;.;.;.;.;.;.;D;.;.;.;.;.;.;T;T
Eigen	Pathogenic	0.73
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Pathogenic	1.0	D
M_CAP	Pathogenic	0.38	D
MetaRNN	Uncertain	0.69	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.60	D
MutationAssessor	Benign	1.1	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	0.88	D
PROVEAN	Uncertain	-3.1	D;.;.;.;.;.;.;.;.;.;D;.;.;D;.;D;.;D;D
REVEL	Pathogenic	0.71
Sift	Uncertain	0.0020	D;.;.;.;.;.;.;.;.;.;D;.;.;D;.;D;.;D;D
Sift4G	Uncertain	0.042	D;.;.;.;.;.;.;.;.;.;D;.;.;D;T;T;T;T;D
Polyphen		1.0	D;.;D;.;.;.;.;.;.;.;D;.;.;.;.;.;.;.;D
Vest4		0.89
MutPred		0.34		Gain of catalytic residue at G119 (P = 0.0056);Gain of catalytic residue at G119 (P = 0.0056);Gain of catalytic residue at G119 (P = 0.0056);Gain of catalytic residue at G119 (P = 0.0056);Gain of catalytic residue at G119 (P = 0.0056);Gain of catalytic residue at G119 (P = 0.0056);Gain of catalytic residue at G119 (P = 0.0056);Gain of catalytic residue at G119 (P = 0.0056);Gain of catalytic residue at G119 (P = 0.0056);Gain of catalytic residue at G119 (P = 0.0056);Gain of catalytic residue at G119 (P = 0.0056);Gain of catalytic residue at G119 (P = 0.0056);Gain of catalytic residue at G119 (P = 0.0056);Gain of catalytic residue at G119 (P = 0.0056);Gain of catalytic residue at G119 (P = 0.0056);Gain of catalytic residue at G119 (P = 0.0056);Gain of catalytic residue at G119 (P = 0.0056);Gain of catalytic residue at G119 (P = 0.0056);Gain of catalytic residue at G119 (P = 0.0056);
MVP		0.94
MPC		1.0
ClinPred		0.96	D
GERP RS		4.5
Varity_R		0.52
gMVP		0.67

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	1.0
SpliceAI score (max)		0.63		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.63		Position offset: 0

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

Publications

LitVar

Other links and lift over

dbSNP: rs1555752203; hg19: chr19-11096081;