rs35089879

Positions:

chr1-108918719-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The ENST00000264126.9(GPSM2):c.1370C>T(p.Thr457Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0159 in 1,612,994 control chromosomes in the GnomAD database, including 558 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.032 ( 166 hom., cov: 31)

Exomes 𝑓: 0.014 ( 392 hom. )

Consequence

GPSM2
ENST00000264126.9 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 0.277

Variant links:

Genes affected

GPSM2 (HGNC:29501): (G protein signaling modulator 2) The protein encoded by this gene belongs to a family of proteins that modulate activation of G proteins, which transduce extracellular signals received by cell surface receptors into integrated cellular responses. The N-terminal half of this protein contains 10 copies of leu-gly-asn (LGN) repeat, and the C-terminal half contains 4 GoLoco motifs, which are involved in guanine nucleotide exchange. This protein may play a role in neuroblast division and in the development of normal hearing. Mutations in this gene are associated with autosomal recessive nonsyndromic deafness (DFNB82). Alternative splicing results in multiple transcript variants. [provided by RefSeq, Mar 2016]

GPSM2 links:

AKNAD1 (HGNC:28398): (AKNA domain containing 1) This gene encodes a protein which contains a domain found in an AT-hook-containing transcription factor. Alternative splicing results in multiple transcript variants. [provided by RefSeq, May 2012]

AKNAD1 links:

CLCC1 (HGNC:29675): (chloride channel CLIC like 1) Predicted to enable chloride channel activity. Predicted to be involved in chloride transport. Located in endoplasmic reticulum and mitochondria-associated endoplasmic reticulum membrane. Implicated in retinitis pigmentosa 32. [provided by Alliance of Genome Resources, Apr 2022]

CLCC1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.001593709).

BP6

Variant 1-108918719-C-T is Benign according to our data. Variant chr1-108918719-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 45564.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0763 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GPSM2	NM_013296.5 linkuse as main transcript	c.1370C>T	p.Thr457Met	missense_variant	12/15	ENST00000264126.9	NP_037428.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GPSM2	ENST00000264126.9 linkuse as main transcript	c.1370C>T	p.Thr457Met	missense_variant	12/15	1	NM_013296.5	ENSP00000264126	P1

Frequencies

GnomAD3 genomes

AF:

0.0314

AC:

4781

AN:

152080

Hom.:

165

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0783

Gnomad AMI

AF:

0.00329

Gnomad AMR

AF:

0.0166

Gnomad ASJ

AF:

0.0297

Gnomad EAS

AF:

0.0141

Gnomad SAS

AF:

0.0605

Gnomad FIN

AF:

0.00217

Gnomad MID

AF:

0.0570

Gnomad NFE

AF:

0.0105

Gnomad OTH

AF:

0.0263

GnomAD3 exomes

AF:

0.0209

AC:

5258

AN:

251392

Hom.:

140

AF XY:

0.0220

AC XY:

2985

AN XY:

135858

show subpopulations

Gnomad AFR exome

AF:

0.0762

Gnomad AMR exome

AF:

0.0106

Gnomad ASJ exome

AF:

0.0305

Gnomad EAS exome

AF:

0.0170

Gnomad SAS exome

AF:

0.0551

Gnomad FIN exome

AF:

0.00152

Gnomad NFE exome

AF:

0.0105

Gnomad OTH exome

AF:

0.0201

GnomAD4 exome

AF:

0.0143

AC:

20888

AN:

1460796

Hom.:

392

Cov.:

AF XY:

0.0155

AC XY:

11279

AN XY:

726782

show subpopulations

Gnomad4 AFR exome

AF:

0.0758

Gnomad4 AMR exome

AF:

0.0117

Gnomad4 ASJ exome

AF:

0.0294

Gnomad4 EAS exome

AF:

0.0155

Gnomad4 SAS exome

AF:

0.0539

Gnomad4 FIN exome

AF:

0.00204

Gnomad4 NFE exome

AF:

0.00927

Gnomad4 OTH exome

AF:

0.0196

GnomAD4 genome

AF:

0.0315

AC:

4797

AN:

152198

Hom.:

166

Cov.:

AF XY:

0.0320

AC XY:

2383

AN XY:

74420

show subpopulations

Gnomad4 AFR

AF:

0.0786

Gnomad4 AMR

AF:

0.0165

Gnomad4 ASJ

AF:

0.0297

Gnomad4 EAS

AF:

0.0141

Gnomad4 SAS

AF:

0.0602

Gnomad4 FIN

AF:

0.00217

Gnomad4 NFE

AF:

0.0106

Gnomad4 OTH

AF:

0.0260

Alfa

AF:

0.0154

Hom.:

Bravo

AF:

0.0335

TwinsUK

AF:

0.00971

AC:

ALSPAC

AF:

0.0127

AC:

ESP6500AA

AF:

0.0744

AC:

328

ESP6500EA

AF:

0.00988

AC:

ExAC

AF:

0.0226

AC:

2742

Asia WGS

AF:

0.0420

AC:

146

AN:

3478

EpiCase

AF:

0.0136

EpiControl

AF:

0.0122

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 07, 2012	Thr457Met in Exon 12 of GPSM2: This variant is not expected to have clinical sig nificance because it has been identified in 7.2% (270/3738) of African American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http: //evs.gs.washington.edu/EVS; dbSNP rs35089879). -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 14, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 30, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Oct 12, 2018	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Chudley-McCullough syndrome

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.078

BayesDel_addAF

Benign

-0.36

BayesDel_noAF

Benign

-0.23

CADD

Benign

DANN

Benign

0.97

DEOGEN2

Benign

0.055

T;T;T

Eigen

Benign

-0.67

Eigen_PC

Benign

-0.58

FATHMM_MKL

Benign

0.090

LIST_S2

Uncertain

0.87

.;.;D

MetaRNN

Benign

0.0016

T;T;T

MetaSVM

Benign

-0.61

MutationAssessor

Benign

0.34

N;N;N

MutationTaster

Benign

0.93

N;N;N

PrimateAI

Benign

0.39

PROVEAN

Benign

-0.78

N;.;N

REVEL

Benign

0.16

Sift

Benign

0.081

T;.;T

Sift4G

Benign

0.083

T;.;T

Polyphen

0.24

B;B;B

Vest4

0.070

MPC

0.25

ClinPred

0.0045

GERP RS

1.4

Varity_R

0.016

gMVP

0.31

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