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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_013296.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GPSM2	NM_013296.5	MANE Select	c.1370C>T	p.Thr457Met	missense	Exon 12 of 15	NP_037428.3
	GPSM2	NM_001321038.2		c.1370C>T	p.Thr457Met	missense	Exon 12 of 15	NP_001307967.1
	GPSM2	NM_001321039.3		c.1370C>T	p.Thr457Met	missense	Exon 12 of 16	NP_001307968.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GPSM2	ENST00000264126.9	TSL:1 MANE Select	c.1370C>T	p.Thr457Met	missense	Exon 12 of 15	ENSP00000264126.3
	GPSM2	ENST00000674914.1		c.1421C>T	p.Thr474Met	missense	Exon 13 of 16	ENSP00000501579.1
	GPSM2	ENST00000675087.1		c.1421C>T	p.Thr474Met	missense	Exon 14 of 17	ENSP00000502020.1

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

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	3	not specified (3)
-	-	1	Chudley-McCullough syndrome (1)

Computational scores

Source: dbNSFP v4.9

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
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
MetaSVM	Benign	-0.61	T
MutationAssessor	Benign	0.34	N
PhyloP100		0.28
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-0.78	N
REVEL	Benign	0.16
Sift	Benign	0.081	T
Sift4G	Benign	0.083	T
Polyphen		0.24	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;