19-11026300-G-C

Position:

• chr19-11026300-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP2

The NM_003072.5(SMARCA4):​c.3169G>C​(p.Glu1057Gln) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,536 control chromosomes in the GnomAD database, with no homozygous occurrence. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: SMARCA4 NM_003072.5 missense, splice_region
• Scores: Splicing: ADA: 0.9990
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.39

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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), SMARCA4. . Gene score misZ: 6.8459 (greater than the threshold 3.09). Trascript score misZ: 8.7957 (greater than threshold 3.09). The gene has 59 curated pathogenic missense variants (we use a threshold of 10). The gene has 56 curated benign missense variants. GenCC has associacion of the gene with uterine corpus sarcoma, Coffin-Siris syndrome 1, intellectual disability, autosomal dominant 16, rhabdoid tumor predisposition syndrome 2, familial rhabdoid tumor, hereditary nonpolyposis colon cancer, Coffin-Siris syndrome.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SMARCA4	NM_001387283.1	c.3169G>C	p.Glu1057Gln	missense_variant, splice_region_variant	23/36	ENST00000646693.2	NP_001374212.1
SMARCA4	NM_003072.5	c.3169G>C	p.Glu1057Gln	missense_variant, splice_region_variant	23/35	ENST00000344626.10	NP_003063.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SMARCA4	ENST00000646693.2	c.3169G>C	p.Glu1057Gln	missense_variant, splice_region_variant	23/36		NM_001387283.1	ENSP00000495368.1
SMARCA4	ENST00000344626.10	c.3169G>C	p.Glu1057Gln	missense_variant, splice_region_variant	23/35	1	NM_003072.5	ENSP00000343896.4
SMARCA4	ENST00000643549.1	c.3169G>C	p.Glu1057Gln	missense_variant, splice_region_variant	23/35			ENSP00000493975.1
SMARCA4	ENST00000541122.6	c.3169G>C	p.Glu1057Gln	missense_variant, splice_region_variant	24/35	5		ENSP00000445036.2
SMARCA4	ENST00000643296.1	c.3169G>C	p.Glu1057Gln	missense_variant, splice_region_variant	23/34			ENSP00000496635.1
SMARCA4	ENST00000644737.1	c.3169G>C	p.Glu1057Gln	missense_variant, splice_region_variant	23/34			ENSP00000495548.1
SMARCA4	ENST00000589677.5	c.3169G>C	p.Glu1057Gln	missense_variant, splice_region_variant	24/35	5		ENSP00000464778.1
SMARCA4	ENST00000643995.1	c.2581G>C	p.Glu861Gln	missense_variant, splice_region_variant	20/32			ENSP00000496004.1
SMARCA4	ENST00000644963.1	c.1813G>C	p.Glu605Gln	missense_variant, splice_region_variant	16/28			ENSP00000495599.1
SMARCA4	ENST00000644065.1	c.1894G>C	p.Glu632Gln	missense_variant, splice_region_variant	16/27			ENSP00000493615.1
SMARCA4	ENST00000642350.1	c.1654G>C	p.Glu552Gln	missense_variant, splice_region_variant	15/27			ENSP00000495355.1
SMARCA4	ENST00000643857.1	c.1522G>C	p.Glu508Gln	missense_variant, splice_region_variant	14/25			ENSP00000494159.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461536 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727092

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

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

Labcorp Genetics (formerly Invitae), Labcorp

Sep 12, 2017

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 do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). 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 glutamic acid with glutamine at codon 1057 of the SMARCA4 protein (p.Glu1057Gln). The glutamic acid residue is highly conserved and there is a small physicochemical difference between glutamic acid and glutamine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Pathogenic	0.16	D
BayesDel_noAF	Uncertain	0.0
CADD	Pathogenic	34
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.48	T;.;T;.;.;.;.;.;.;.;T;.;.;.;.;.;T;T;.;.;.;.
Eigen	Uncertain	0.33
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	0.97	.;D;.;.;.;.;D;.;.;.;D;.;D;D;D;D;D;D;D;D;D;D
M_CAP	Uncertain	0.26	D
MetaRNN	Uncertain	0.48	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	-0.091	T
MutationAssessor	Uncertain	2.5	M;.;.;.;M;M;.;M;M;M;M;M;M;M;M;M;.;.;.;.;.;.
PrimateAI	Uncertain	0.75	T
PROVEAN	Uncertain	-2.4	N;.;.;.;.;.;.;.;.;.;N;.;N;.;N;.;.;N;.;.;.;.
REVEL	Uncertain	0.49
Sift	Uncertain	0.0070	D;.;.;.;.;.;.;.;.;.;D;.;D;.;D;.;.;D;.;.;.;.
Sift4G	Uncertain	0.046	D;.;.;.;.;.;.;.;.;.;D;.;D;D;D;D;D;D;.;.;.;.
Polyphen		0.030	B;.;B;.;.;.;.;.;.;.;B;.;.;.;.;.;.;B;.;.;.;.
Vest4		0.60
MutPred		0.26		Loss of disorder (P = 0.1208);Loss of disorder (P = 0.1208);Loss of disorder (P = 0.1208);Loss of disorder (P = 0.1208);Loss of disorder (P = 0.1208);Loss of disorder (P = 0.1208);Loss of disorder (P = 0.1208);Loss of disorder (P = 0.1208);Loss of disorder (P = 0.1208);Loss of disorder (P = 0.1208);Loss of disorder (P = 0.1208);Loss of disorder (P = 0.1208);Loss of disorder (P = 0.1208);Loss of disorder (P = 0.1208);Loss of disorder (P = 0.1208);Loss of disorder (P = 0.1208);.;Loss of disorder (P = 0.1208);.;.;.;.;
MVP		0.80
MPC		2.8
ClinPred		0.96	D
GERP RS		4.5
Varity_R		0.51
gMVP		0.94

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.94
SpliceAI score (max)		0.43		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.43		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: rs1555781050; hg19: chr19-11136976;