19-11041318-G-C

Position:

• chr19-11041318-G-C

Variant summary

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

The NM_003072.5(SMARCA4):​c.4182G>C​(p.Glu1394Asp) 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. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SMARCA4 NM_003072.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0450

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]

SMARCA4 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 1 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=0.07169545).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SMARCA4	NM_001387283.1	c.4278G>C	p.Glu1426Asp	missense_variant	31/36	ENST00000646693.2	NP_001374212.1
SMARCA4	NM_003072.5	c.4182G>C	p.Glu1394Asp	missense_variant	30/35	ENST00000344626.10	NP_003063.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SMARCA4	ENST00000646693.2	c.4278G>C	p.Glu1426Asp	missense_variant	31/36		NM_001387283.1	ENSP00000495368.1
SMARCA4	ENST00000344626.10	c.4182G>C	p.Glu1394Asp	missense_variant	30/35	1	NM_003072.5	ENSP00000343896.4
SMARCA4	ENST00000643549.1	c.4188G>C	p.Glu1396Asp	missense_variant	30/35			ENSP00000493975.1
SMARCA4	ENST00000541122.6	c.4092G>C	p.Glu1364Asp	missense_variant	30/35	5		ENSP00000445036.2
SMARCA4	ENST00000643296.1	c.4092G>C	p.Glu1364Asp	missense_variant	29/34			ENSP00000496635.1
SMARCA4	ENST00000644737.1	c.4092G>C	p.Glu1364Asp	missense_variant	29/34			ENSP00000495548.1
SMARCA4	ENST00000589677.5	c.4092G>C	p.Glu1364Asp	missense_variant	30/35	5		ENSP00000464778.1
SMARCA4	ENST00000643995.1	c.3603G>C	p.Glu1201Asp	missense_variant	27/32			ENSP00000496004.1
SMARCA4	ENST00000644963.1	c.2835G>C	p.Glu945Asp	missense_variant	23/28			ENSP00000495599.1
SMARCA4	ENST00000644065.1	c.2817G>C	p.Glu939Asp	missense_variant	22/27			ENSP00000493615.1
SMARCA4	ENST00000642350.1	c.2676G>C	p.Glu892Asp	missense_variant	22/27			ENSP00000495355.1
SMARCA4	ENST00000643857.1	c.2544G>C	p.Glu848Asp	missense_variant	21/25			ENSP00000494159.1
SMARCA4	ENST00000538456.4	c.348G>C	p.Glu116Asp	missense_variant	4/8	3		ENSP00000495197.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

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

Jan 25, 2022

The p.E1426D variant (also known as c.4278G>C), located in coding exon 30 of the SMARCA4 gene, results from a G to C substitution at nucleotide position 4278. The glutamic acid at codon 1426 is replaced by aspartic acid, an amino acid with highly similar properties. Missense and in-frame variants in SMARCA4 are known to cause neurodevelopmental disorders; however, such associations with rhabdoid tumor predisposition syndrome including small cell carcinoma of the ovary-hypercalcemic type (SCCOHT) are exceedingly rare (Kosho T et al. Am J Med Genet C Semin Med Genet. 2014 Sep;166C(3):262-75; Jelinic P et al. Nat Genet. 2014 May;46(5):424-6). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the supporting evidence, the association of this alteration with Coffin-Siris syndrome is unknown; however, the association of this alteration with rhabdoid tumor predisposition syndrome syndrome is unlikely. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	0.0019	T
BayesDel_noAF	Benign	-0.24
CADD	Uncertain	24
DANN	Benign	0.36
DEOGEN2	Benign	0.19	T;.;T;.;.;.;.;.;.;.;T;.;.;.;.;.;T;T;.;.;.;.;.
Eigen	Benign	-0.10
Eigen_PC	Benign	-0.045
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.90	.;D;.;.;.;.;D;.;.;.;D;.;D;D;D;D;D;D;D;D;D;D;D
M_CAP	Benign	0.045	D
MetaRNN	Benign	0.072	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.31	N;.;.;.;.;.;.;.;.;.;N;.;.;.;.;.;.;.;.;.;.;.;.
PrimateAI	Uncertain	0.78	T
PROVEAN	Benign	0.23	N;.;.;.;.;.;.;.;.;.;N;.;.;.;N;.;.;.;.;.;.;.;.
REVEL	Uncertain	0.33
Sift	Benign	1.0	T;.;.;.;.;.;.;.;.;.;T;.;.;.;T;.;.;.;.;.;.;.;.
Sift4G	Benign	1.0	T;.;.;.;.;.;.;.;.;.;T;.;T;T;T;T;T;T;.;.;.;.;.
Polyphen		0.0040	B;.;B;.;.;.;.;.;.;.;B;.;.;.;.;.;.;B;.;.;.;.;.
Vest4		0.30
MutPred		0.24		.;.;Loss of loop (P = 0.0288);.;.;.;.;.;.;.;.;.;.;.;.;.;.;Loss of loop (P = 0.0288);.;.;.;.;.;
MVP		0.65
MPC		0.92
ClinPred		0.13	T
GERP RS		2.1
RBP_binding_hub_radar		0.97
RBP_regulation_power_radar		2.7
Varity_R		0.075
gMVP		0.79

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-11151994;