chr17-40631658-T-G

Position:

• chr17-40631658-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_003079.5(SMARCE1):​c.750A>C​(p.Glu250Asp) 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: SMARCE1 NM_003079.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: -0.321

Genes affected

SMARCE1 (HGNC:11109): (SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily e, member 1) The protein encoded by this gene is part of the large ATP-dependent chromatin remodeling complex SWI/SNF, which is required for transcriptional activation of genes normally repressed by chromatin. The encoded protein, either alone or when in the SWI/SNF complex, can bind to 4-way junction DNA, which is thought to mimic the topology of DNA as it enters or exits the nucleosome. The protein contains a DNA-binding HMG domain, but disruption of this domain does not abolish the DNA-binding or nucleosome-displacement activities of the SWI/SNF complex. Unlike most of the SWI/SNF complex proteins, this protein has no yeast counterpart. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.11559191).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SMARCE1	NM_003079.5	c.750A>C	p.Glu250Asp	missense_variant	9/11	ENST00000348513.12	NP_003070.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SMARCE1	ENST00000348513.12	c.750A>C	p.Glu250Asp	missense_variant	9/11	1	NM_003079.5	ENSP00000323967	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 27

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial meningioma Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 28, 2019

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 (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with SMARCE1-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change replaces glutamic acid with aspartic acid at codon 250 of the SMARCE1 protein (p.Glu250Asp). The glutamic acid residue is moderately conserved and there is a small physicochemical difference between glutamic acid and aspartic acid. -

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 27, 2019

The p.E250D variant (also known as c.750A>C), located in coding exon 8 of the SMARCE1 gene, results from an A to C substitution at nucleotide position 750. The glutamic acid at codon 250 is replaced by aspartic acid, an amino acid with highly similar properties. This amino acid position is highly conserved through mammals, but not in lower in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. 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	Benign	0.10
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	8.5
DANN	Uncertain	0.99
DEOGEN2	Benign	0.16	T;.;.;.;.;.;.;.;.;T;.;.;T;.;.;.;.;.;.;.
Eigen	Benign	-0.31
Eigen_PC	Benign	-0.29
FATHMM_MKL	Benign	0.48	N
LIST_S2	Benign	0.85	.;.;T;D;.;T;T;T;T;D;D;.;D;D;T;T;T;T;D;T
M_CAP	Benign	0.0043	T
MetaRNN	Benign	0.12	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	1.1	L;.;.;.;L;.;.;.;.;L;.;L;.;.;.;L;.;.;.;.
MutationTaster	Benign	0.97	D;D;D;D;D;D;D
PrimateAI	Uncertain	0.72	T
PROVEAN	Benign	-2.0	N;.;.;.;.;.;.;.;N;.;.;.;N;.;.;.;.;.;.;.
REVEL	Benign	0.12
Sift	Benign	0.24	T;.;.;.;.;.;.;.;T;.;.;.;T;.;.;.;.;.;.;.
Sift4G	Benign	0.17	T;.;.;.;.;T;.;T;T;.;.;.;T;T;.;.;.;.;.;.
Polyphen		0.0050	B;.;.;.;.;.;.;.;.;B;.;.;.;.;.;.;.;.;.;.
Vest4		0.14
MutPred		0.13		Loss of helix (P = 0.0795);.;.;.;Loss of helix (P = 0.0795);.;.;.;.;Loss of helix (P = 0.0795);.;Loss of helix (P = 0.0795);.;.;.;Loss of helix (P = 0.0795);.;Loss of helix (P = 0.0795);.;.;
MVP		0.47
MPC		0.52
ClinPred		0.45	T
GERP RS		-0.043
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.25
gMVP		0.12

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: rs1555605350; hg19: chr17-38787910;