rs142193069

Positions:

chr17-40628942-C-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_003079.5(SMARCE1):c.1079G>A(p.Gly360Asp) variant causes a missense change. The variant allele was found at a frequency of 0.00276 in 1,613,810 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G360R) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0014 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0029 ( 11 hom. )

Consequence

SMARCE1
NM_003079.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1B:6

Conservation

PhyloP100: 6.82

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.013834089).

BP6

Variant 17-40628942-C-T is Benign according to our data. Variant chr17-40628942-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 239487.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-40628942-C-T is described in Lovd as [Likely_benign]. Variant chr17-40628942-C-T is described in Lovd as [Benign].

BS2

High AC in GnomAd4 at 214 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SMARCE1	NM_003079.5 linkuse as main transcript	c.1079G>A	p.Gly360Asp	missense_variant	11/11	ENST00000348513.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SMARCE1	ENST00000348513.12 linkuse as main transcript	c.1079G>A	p.Gly360Asp	missense_variant	11/11	1	NM_003079.5	P1	Q969G3-1

Frequencies

GnomAD3 genomes

AF:

0.00141

AC:

214

AN:

152116

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000362

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000830

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00268

Gnomad OTH

AF:

0.00144

GnomAD3 exomes

AF:

0.00147

AC:

368

AN:

251080

Hom.:

AF XY:

0.00157

AC XY:

213

AN XY:

135702

show subpopulations

Gnomad AFR exome

AF:

0.000492

Gnomad AMR exome

AF:

0.000492

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00114

Gnomad FIN exome

AF:

0.000277

Gnomad NFE exome

AF:

0.00260

Gnomad OTH exome

AF:

0.00114

GnomAD4 exome

AF:

0.00290

AC:

4241

AN:

1461576

Hom.:

Cov.:

AF XY:

0.00274

AC XY:

1995

AN XY:

727104

show subpopulations

Gnomad4 AFR exome

AF:

0.000448

Gnomad4 AMR exome

AF:

0.000470

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00148

Gnomad4 FIN exome

AF:

0.000225

Gnomad4 NFE exome

AF:

0.00354

Gnomad4 OTH exome

AF:

0.00204

GnomAD4 genome

AF:

0.00141

AC:

214

AN:

152234

Hom.:

Cov.:

AF XY:

0.00132

AC XY:

AN XY:

74432

show subpopulations

Gnomad4 AFR

AF:

0.000361

Gnomad4 AMR

AF:

0.000653

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000830

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00268

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.00212

Hom.:

Bravo

AF:

0.00148

TwinsUK

AF:

0.00270

AC:

ALSPAC

AF:

0.00259

AC:

ESP6500AA

AF:

0.000681

AC:

ESP6500EA

AF:

0.00209

AC:

ExAC

AF:

0.00143

AC:

174

Asia WGS

AF:

0.00115

AC:

AN:

3478

EpiCase

AF:

0.00191

EpiControl

AF:

0.00213

ClinVar

Significance: Benign/Likely benign

Submissions summary: Uncertain:1Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:2

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2024	SMARCE1: BS1, BS2 -
Uncertain significance, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The SMARCE1 p.Gly360Asp variant was not identified in the literature nor was it identified in Cosmic. The variant was identified in dbSNP (ID: rs142193069), LOVd 3.0 and in ClinVar (classified as likely benign by Invitae and as a VUS by Genetics Services University of Chicago and Ambry Genetics). The variant was also identified in control databases in 408 of 282474 chromosomes (1 homozygous) at a frequency of 0.001444 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017) and was observed in the following populations: European (non-Finnish) in 328 of 128822 chromosomes (freq: 0.002546), South Asian in 35 of 30614 chromosomes (freq: 0.001143), Other in 8 of 7216 chromosomes (freq: 0.001109), Latino in 18 of 35434 chromosomes (freq: 0.000508), African in 12 of 24968 chromosomes (freq: 0.000481) and European (Finnish) in 7 of 25098 chromosomes (freq: 0.000279); it was not observed in the Ashkenazi Jewish and East Asian populations. The variant occurs outside of the splicing consensus sequence and 3 of 4 in silico or computational prediction software programs (MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. The p.Gly360 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 21, 2021	This variant is associated with the following publications: (PMID: 25169753) -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Sep 10, 2018

- -

SMARCE1-related disorder

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 20, 2020

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Familial meningioma

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Hereditary cancer-predisposing syndrome

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 21, 2019

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

Benign

0.11

BayesDel_addAF

Benign

-0.38

BayesDel_noAF

Benign

-0.33

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.085

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

Eigen

Uncertain

0.64

Eigen_PC

Uncertain

0.66

FATHMM_MKL

Pathogenic

1.0

M_CAP

Benign

0.017

MetaRNN

Benign

0.014

T;T;T;T;T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.81

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

MutationTaster

Benign

1.0

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

PrimateAI

Pathogenic

0.80

PROVEAN

Benign

-0.070

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

REVEL

Benign

0.20

Sift

Uncertain

0.0070

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

Sift4G

Benign

0.52

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

Polyphen

1.0

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

Vest4

0.58

MVP

0.27

MPC

1.7

ClinPred

0.024

GERP RS

5.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.30

gMVP

0.049

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