Genetic Variant GPR35:p.Thr108Met (chr2-240630275-C-T) – ACMG Classification: Benign (-20 pts)

Variant summary

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

The NM_005301.5(GPR35):c.323C>T(p.Thr108Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.175 in 1,563,974 control chromosomes in the GnomAD database, including 25,182 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

Frequency

Genomes: 𝑓 0.18 ( 2689 hom., cov: 33)

Exomes 𝑓: 0.17 ( 22493 hom. )

Consequence

GPR35
NM_005301.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -0.797

Variant links:

Genes affected

GPR35 (HGNC:4492): (G protein-coupled receptor 35) Enables C-X-C chemokine receptor activity. Involved in several processes, including chemokine-mediated signaling pathway; negative regulation of voltage-gated calcium channel activity; and positive regulation of cytosolic calcium ion concentration. Is integral component of plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

GPR35 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0054234266).

BP6

Variant 2-240630275-C-T is Benign according to our data. Variant chr2-240630275-C-T is described in ClinVar as [Benign]. Clinvar id is 1234784.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.218 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GPR35	NM_005301.5 link	c.323C>T	p.Thr108Met	missense_variant	Exon 2 of 2	ENST00000407714.2	NP_005292.2	Q9HC97-1B2RA17A8K2J1
GPR35	NM_001195381.3 link	c.416C>T	p.Thr139Met	missense_variant	Exon 6 of 6		NP_001182310.1	Q9HC97-2
GPR35	NM_001195382.3 link	c.416C>T	p.Thr139Met	missense_variant	Exon 6 of 6		NP_001182311.1	Q9HC97-2A8K2J1
GPR35	NM_001394730.1 link	c.416C>T	p.Thr139Met	missense_variant	Exon 6 of 6		NP_001381659.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GPR35	ENST00000407714.2 link	c.323C>T	p.Thr108Met	missense_variant	Exon 2 of 2	1	NM_005301.5	ENSP00000384263.1		Q9HC97-1

Frequencies

GnomAD3 genomes

AF:

0.184

AC:

28056

AN:

152120

Hom.:

2685

Cov.:

show subpopulations

Gnomad AFR

AF:

0.222

Gnomad AMI

AF:

0.202

Gnomad AMR

AF:

0.145

Gnomad ASJ

AF:

0.115

Gnomad EAS

AF:

0.0784

Gnomad SAS

AF:

0.114

Gnomad FIN

AF:

0.252

Gnomad MID

AF:

0.111

Gnomad NFE

AF:

0.177

Gnomad OTH

AF:

0.147

GnomAD3 exomes

AF:

0.164

AC:

34813

AN:

212636

Hom.:

3102

AF XY:

0.160

AC XY:

18446

AN XY:

115068

show subpopulations

Gnomad AFR exome

AF:

0.226

Gnomad AMR exome

AF:

0.126

Gnomad ASJ exome

AF:

0.126

Gnomad EAS exome

AF:

0.0831

Gnomad SAS exome

AF:

0.118

Gnomad FIN exome

AF:

0.253

Gnomad NFE exome

AF:

0.185

Gnomad OTH exome

AF:

0.154

GnomAD4 exome

AF:

0.174

AC:

245578

AN:

1411736

Hom.:

22493

Cov.:

AF XY:

0.171

AC XY:

119427

AN XY:

697364

show subpopulations

Gnomad4 AFR exome

AF:

0.218

Gnomad4 AMR exome

AF:

0.127

Gnomad4 ASJ exome

AF:

0.123

Gnomad4 EAS exome

AF:

0.0723

Gnomad4 SAS exome

AF:

0.113

Gnomad4 FIN exome

AF:

0.249

Gnomad4 NFE exome

AF:

0.182

Gnomad4 OTH exome

AF:

0.165

GnomAD4 genome

AF:

0.184

AC:

28063

AN:

152238

Hom.:

2689

Cov.:

AF XY:

0.183

AC XY:

13632

AN XY:

74426

show subpopulations

Gnomad4 AFR

AF:

0.222

Gnomad4 AMR

AF:

0.145

Gnomad4 ASJ

AF:

0.115

Gnomad4 EAS

AF:

0.0774

Gnomad4 SAS

AF:

0.114

Gnomad4 FIN

AF:

0.252

Gnomad4 NFE

AF:

0.177

Gnomad4 OTH

AF:

0.145

Alfa

AF:

0.172

Hom.:

2115

Bravo

AF:

0.177

TwinsUK

AF:

0.176

AC:

652

ALSPAC

AF:

0.176

AC:

680

ESP6500AA

AF:

0.225

AC:

993

ESP6500EA

AF:

0.172

AC:

1478

ExAC

AF:

0.165

AC:

19883

Asia WGS

AF:

0.122

AC:

424

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Feb 18, 2020

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 23128233, 26610302) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Benign

-0.64

BayesDel_noAF

Benign

-0.55

CADD

Benign

7.4

DANN

Uncertain

0.99

DEOGEN2

Benign

0.076

T;T;.;T;T

Eigen

Benign

-0.97

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.059

LIST_S2

Benign

0.52

.;.;T;.;T

MetaRNN

Benign

0.0054

T;T;T;T;T

MetaSVM

Benign

-0.77

MutationAssessor

Benign

1.5

L;L;.;L;L

PrimateAI

Benign

0.45

PROVEAN

Uncertain

-3.3

D;D;.;D;.

REVEL

Benign

0.25

Sift

Benign

0.18

T;T;.;T;.

Sift4G

Benign

0.14

T;T;T;T;T

Polyphen

0.96

P;P;.;P;P

Vest4

0.085

MPC

0.58

ClinPred

0.079

GERP RS

-7.4

Varity_R

0.060

gMVP

0.54

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