17-40628934-T-C

Position:

• chr17-40628934-T-C

Variant summary

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

The NM_003079.5(SMARCE1):​c.1087A>G​(p.Thr363Ala) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: SMARCE1 NM_003079.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 4.33

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=0.113253266).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SMARCE1	NM_003079.5	c.1087A>G	p.Thr363Ala	missense_variant	11/11	ENST00000348513.12	NP_003070.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SMARCE1	ENST00000348513.12	c.1087A>G	p.Thr363Ala	missense_variant	11/11	1	NM_003079.5	ENSP00000323967	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

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

Aug 09, 2022

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. ClinVar contains an entry for this variant (Variation ID: 463414). This variant has not been reported in the literature in individuals affected with SMARCE1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces threonine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 363 of the SMARCE1 protein (p.Thr363Ala). -

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 27, 2022

The p.T363A variant (also known as c.1087A>G), located in coding exon 10 of the SMARCE1 gene, results from an A to G substitution at nucleotide position 1087. The threonine at codon 363 is replaced by alanine, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Missense and in-frame variants in SMARCE1 are known to cause neurodevelopmental disorders; however, such associations with increased risk of meningiomas are exceedingly rare (Kosho T et al. Am J Med Genet C Semin Med Genet. 2014 Sep;166C(3):262-75; Smith JM et al. Nat Genet. 2013 Mar;45(3):295-8). Based on the supporting evidence, the association of this alteration with an increased risk of Coffin-Siris syndrome is unknown; however, the association of this alteration with an increased risk of meningiomas is unlikely. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.068
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	17
DANN	Uncertain	0.99
DEOGEN2	Benign	0.099	T;.;.;.;T;.;T;.
Eigen	Benign	-0.25
Eigen_PC	Benign	-0.031
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.81	.;.;T;T;T;T;T;T
M_CAP	Benign	0.0077	T
MetaRNN	Benign	0.11	T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.81	L;.;.;.;L;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-0.30	N;.;.;.;.;.;N;.
REVEL	Benign	0.065
Sift	Benign	0.10	T;.;.;.;.;.;T;.
Sift4G	Benign	0.55	T;.;.;.;.;.;T;T
Polyphen		0.0010	B;.;.;.;B;.;.;.
Vest4		0.32
MutPred		0.11		Loss of phosphorylation at T363 (P = 9e-04);.;.;.;Loss of phosphorylation at T363 (P = 9e-04);.;.;.;
MVP		0.18
MPC		0.67
ClinPred		0.55	D
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.057
gMVP		0.10

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: rs1555605096; hg19: chr17-38785186;