1-108918719-C-T

Variant names:

• chr1-108918719-C-T
• rs35089879
• NM_013296.5:c.1370C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_013296.5(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. 16/21 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 NM_013296.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.277
• Publications: 10 publications found

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]

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]

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]

ACMG classification

Our verdict: Benign. The variant received -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 Benign/Likely_benign. ClinVar VariationId 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 rank	MANE	Protein	UniProt
GPSM2	NM_013296.5	c.1370C>T	p.Thr457Met	missense_variant	Exon 12 of 15	ENST00000264126.9	NP_037428.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GPSM2	ENST00000264126.9	c.1370C>T	p.Thr457Met	missense_variant	Exon 12 of 15	1	NM_013296.5	ENSP00000264126.3

Frequencies

GnomAD3 genomes AF: 0.0314 AC: 4781 AN: 152080 Hom.: 165 Cov.: 31

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

GnomAD2 exomes AF: 0.0209 AC: 5258 AN: 251392 AF XY: 0.0220

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 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.: 30 AF XY: 0.0155 AC XY: 11279 AN XY: 726782

African (AFR) AF: 0.0758 AC: 2532 AN: 33422

American (AMR) AF: 0.0117 AC: 524 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.0294 AC: 767 AN: 26124

East Asian (EAS) AF: 0.0155 AC: 616 AN: 39652

South Asian (SAS) AF: 0.0539 AC: 4648 AN: 86216

European-Finnish (FIN) AF: 0.00204 AC: 109 AN: 53418

Middle Eastern (MID) AF: 0.0373 AC: 215 AN: 5760

European-Non Finnish (NFE) AF: 0.00927 AC: 10295 AN: 1111132

Other (OTH) AF: 0.0196 AC: 1182 AN: 60354

GnomAD4 genome AF: 0.0315 AC: 4797 AN: 152198 Hom.: 166 Cov.: 31 AF XY: 0.0320 AC XY: 2383 AN XY: 74420

African (AFR) AF: 0.0786 AC: 3262 AN: 41516

American (AMR) AF: 0.0165 AC: 253 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.0297 AC: 103 AN: 3468

East Asian (EAS) AF: 0.0141 AC: 73 AN: 5182

South Asian (SAS) AF: 0.0602 AC: 290 AN: 4820

European-Finnish (FIN) AF: 0.00217 AC: 23 AN: 10602

Middle Eastern (MID) AF: 0.0578 AC: 17 AN: 294

European-Non Finnish (NFE) AF: 0.0106 AC: 718 AN: 68002

Other (OTH) AF: 0.0260 AC: 55 AN: 2114

Alfa AF: 0.0172 Hom.: 140

Bravo AF: 0.0335

TwinsUK AF: 0.00971 AC: 36

ALSPAC AF: 0.0127 AC: 49

ESP6500AA AF: 0.0744 AC: 328

ESP6500EA AF: 0.00988 AC: 85

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

Submissions by phenotype

not specified Benign:3

Mar 14, 2016

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

May 07, 2012

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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). -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:3

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 12, 2018

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Chudley-McCullough syndrome Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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	T
BayesDel_noAF	Benign	-0.23
CADD	Benign	18
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	N
LIST_S2	Uncertain	0.87	.;.;D
MetaRNN	Benign	0.0016	T;T;T
MetaSVM	Benign	-0.61	T
MutationAssessor	Benign	0.34	N;N;N
PhyloP100		0.28
PrimateAI	Benign	0.39	T
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	T
GERP RS		1.4
Varity_R		0.016
gMVP		0.31
Mutation Taster		=99/1	polymorphism (auto)

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

Other links and lift over

dbSNP: rs35089879; hg19: chr1-109461341;