rs1413987767

Variant names:

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2PP3BP6

The NM_003079.5(SMARCE1):c.821G>A(p.Cys274Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.000000686 in 1,458,522 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

SMARCE1
NM_003079.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:1

Conservation

PhyloP100: 7.10

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 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.811

BP6

Variant 17-40630920-C-T is Benign according to our data. Variant chr17-40630920-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 532247.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMARCE1	NM_003079.5 link	c.821G>A	p.Cys274Tyr	missense_variant	Exon 10 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.821G>A	p.Cys274Tyr	missense_variant	Exon 10 of 11	1	NM_003079.5	ENSP00000323967.6	Q969G3-1
ENSG00000264058	ENST00000476049.1 link	n.*1169G>A		non_coding_transcript_exon_variant	Exon 12 of 13	5		ENSP00000463483.1
ENSG00000264058	ENST00000476049.1 link	n.*1169G>A		3_prime_UTR_variant	Exon 12 of 13	5		ENSP00000463483.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.86e-7

AC:

AN:

1458522

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

725748

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.:

Alfa

AF:

0.0000708

Hom.:

Bravo

AF:

0.00000756

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Familial meningioma

Uncertain:1

Sep 17, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. 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 expected to disrupt SMARCE1 protein function. ClinVar contains an entry for this variant (Variation ID: 532247). 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 cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 274 of the SMARCE1 protein (p.Cys274Tyr). -

Hereditary cancer-predisposing syndrome

Benign:1

Feb 13, 2023

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Uncertain

0.067

BayesDel_noAF

Benign

-0.14

CADD

Pathogenic

DANN

Benign

0.90

DEOGEN2

Uncertain

0.49

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

Eigen

Pathogenic

0.69

Eigen_PC

Uncertain

0.65

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.78

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

M_CAP

Uncertain

0.12

MetaRNN

Pathogenic

0.81

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

MetaSVM

Benign

-0.34

MutationAssessor

Uncertain

2.8

M;.;.;.;M;.;.;.;.;M;.;M;.;.;.;M;.;.;.;.

PrimateAI

Pathogenic

0.86

PROVEAN

Pathogenic

-8.8

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

REVEL

Uncertain

0.37

Sift

Uncertain

0.0010

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

Sift4G

Uncertain

0.0030

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

Polyphen

1.0

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

Vest4

0.95

MutPred

0.51

Gain of loop (P = 0.0312);.;.;.;Gain of loop (P = 0.0312);.;.;.;.;Gain of loop (P = 0.0312);.;Gain of loop (P = 0.0312);.;.;.;Gain of loop (P = 0.0312);.;Gain of loop (P = 0.0312);.;.;

MVP

0.38

MPC

1.8

ClinPred

1.0

GERP RS

5.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.93

gMVP

0.57

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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