rs114594206

Positions:

• chr19-10989338-C-G
• chr19-10989338-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP2 BP4

The NM_001387283.1(SMARCA4):​c.1140C>G​(p.His380Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 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. H380Y) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SMARCA4 NM_001387283.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.625

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 2 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). GenCC has associacion of 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.35717344).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SMARCA4	NM_001387283.1	c.1140C>G	p.His380Gln	missense_variant	7/36	ENST00000646693.2
SMARCA4	NM_003072.5	c.1140C>G	p.His380Gln	missense_variant	7/35	ENST00000344626.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SMARCA4	ENST00000646693.2	c.1140C>G	p.His380Gln	missense_variant	7/36		NM_001387283.1
SMARCA4	ENST00000344626.10	c.1140C>G	p.His380Gln	missense_variant	7/35	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

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 29, 2019

The p.H380Q variant (also known as c.1140C>G), located in coding exon 6 of the SMARCA4 gene, results from a C to G substitution at nucleotide position 1140. The histidine at codon 380 is replaced by glutamine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.63
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.030
CADD	Benign	20
DANN	Benign	0.89
DEOGEN2	Uncertain	0.59	D;.;T;.;.;.;.;.;.;.;D;.;.;.;.;.;T;T
Eigen	Benign	-0.43
Eigen_PC	Benign	-0.34
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.96	.;D;.;.;.;.;D;.;.;.;D;.;D;D;D;D;D;D
M_CAP	Pathogenic	0.41	D
MetaRNN	Benign	0.36	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	-0.16	T
MutationAssessor	Benign	1.3	L;.;.;.;L;L;.;L;L;L;L;L;L;L;L;L;.;.
MutationTaster	Benign	0.93	D;D;D;D;D;D;D;D;D
PrimateAI	Pathogenic	0.88	D
PROVEAN	Uncertain	-2.9	D;.;.;.;.;.;.;.;.;.;D;.;D;.;D;.;D;D
REVEL	Uncertain	0.53
Sift	Benign	0.36	T;.;.;.;.;.;.;.;.;.;T;.;T;.;T;.;T;T
Sift4G	Benign	0.36	T;.;.;.;.;.;.;.;.;.;T;.;T;T;T;T;T;T
Polyphen		0.0070	B;.;B;.;.;.;.;.;.;.;B;.;.;.;.;.;.;B
Vest4		0.67
MutPred		0.28		Gain of disorder (P = 0.0284);Gain of disorder (P = 0.0284);Gain of disorder (P = 0.0284);Gain of disorder (P = 0.0284);Gain of disorder (P = 0.0284);Gain of disorder (P = 0.0284);Gain of disorder (P = 0.0284);Gain of disorder (P = 0.0284);Gain of disorder (P = 0.0284);Gain of disorder (P = 0.0284);Gain of disorder (P = 0.0284);Gain of disorder (P = 0.0284);Gain of disorder (P = 0.0284);Gain of disorder (P = 0.0284);Gain of disorder (P = 0.0284);Gain of disorder (P = 0.0284);Gain of disorder (P = 0.0284);Gain of disorder (P = 0.0284);
MVP		0.85
MPC		1.5
ClinPred		0.55	D
GERP RS		0.56
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.47
gMVP		0.91

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: rs114594206; hg19: chr19-11100014;