chr17-40636433-C-G

Variant names:

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1PM2

The NM_003079.5(SMARCE1):c.331G>C(p.Glu111Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,038 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

SMARCE1
NM_003079.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 7.73

Variant links:

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]

SMARCE1 links:

ENSG00000264058 (HGNC:):

ENSG00000264058 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM1

In a DNA_binding_region HMG box (size 68) in uniprot entity SMCE1_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_003079.5

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMARCE1	NM_003079.5 link	c.331G>C	p.Glu111Gln	missense_variant	Exon 6 of 11	ENST00000348513.12	NP_003070.3	Q969G3-1A0A024R1S7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
SMARCE1	ENST00000348513.12 link	c.331G>C	p.Glu111Gln	missense_variant	Exon 6 of 11	1	NM_003079.5	ENSP00000323967.6	Q969G3-1
ENSG00000264058	ENST00000476049.1 link	n.*679G>C		non_coding_transcript_exon_variant	Exon 8 of 13	5		ENSP00000463483.1
ENSG00000264058	ENST00000476049.1 link	n.*679G>C		3_prime_UTR_variant	Exon 8 of 13	5		ENSP00000463483.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.85e-7

AC:

AN:

1460038

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726388

show subpopulations

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:

9.00e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Familial meningioma

Uncertain:1

Feb 14, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glutamic acid, which is acidic and polar, with glutamine, which is neutral and polar, at codon 111 of the SMARCE1 protein (p.Glu111Gln). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with SMARCE1-related conditions. ClinVar contains an entry for this variant (Variation ID: 239492). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt SMARCE1 protein function with a negative predictive value of 80%. 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. -

Hereditary cancer-predisposing syndrome

Uncertain:1

Sep 19, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.E111Q variant (also known as c.331G>C), located in coding exon 5 of the SMARCE1 gene, results from a G to C substitution at nucleotide position 331. The glutamic acid at codon 111 is replaced by glutamine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.92

BayesDel_addAF

Pathogenic

0.28

BayesDel_noAF

Pathogenic

0.17

CADD

Pathogenic

DANN

Uncertain

0.98

DEOGEN2

Uncertain

0.78

D;.;.;.;.;.;.;.;.;D;.;.;D;.;.;.;.;.;.;D;.;D

Eigen

Uncertain

0.37

Eigen_PC

Uncertain

0.49

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Uncertain

0.94

.;.;D;D;.;D;D;D;D;D;D;.;D;D;D;D;D;D;D;D;D;D

M_CAP

Uncertain

0.26

MetaRNN

Uncertain

0.68

D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D

MetaSVM

Pathogenic

0.97

MutationAssessor

Benign

1.5

L;.;.;.;L;.;.;.;.;L;.;L;.;.;.;L;.;.;.;.;.;.

PrimateAI

Pathogenic

0.85

PROVEAN

Uncertain

-2.4

N;.;.;.;.;.;.;.;N;.;.;.;N;.;.;.;.;.;.;.;.;.

REVEL

Pathogenic

0.71

Sift

Benign

0.15

T;.;.;.;.;.;.;.;T;.;.;.;D;.;.;.;.;.;.;.;.;.

Sift4G

Benign

0.096

T;.;.;.;.;T;.;T;T;.;.;.;T;T;.;.;.;.;.;.;.;T

Polyphen

0.54

P;.;.;.;.;.;.;.;.;P;.;.;P;.;.;.;.;.;.;.;.;.

Vest4

0.60

MutPred

0.51

Loss of helix (P = 0.0626);.;.;.;Loss of helix (P = 0.0626);.;.;.;.;Loss of helix (P = 0.0626);.;Loss of helix (P = 0.0626);.;.;.;Loss of helix (P = 0.0626);.;Loss of helix (P = 0.0626);.;.;.;Loss of helix (P = 0.0626);

MVP

0.91

MPC

2.6

ClinPred

0.90

GERP RS

5.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.8

Varity_R

0.50

gMVP

0.92

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over