chr2-240630275-C-T

Position:

• chr2-240630275-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

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 same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.18 (2689 hom., cov: 33)
  • Exomes 𝑓: 0.17 (22493 hom.)
• Consequence: GPR35 NM_005301.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.797

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]

ACMG classification

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/exons	MANE	Protein	UniProt
GPR35	NM_005301.5	c.323C>T	p.Thr108Met	missense_variant	2/2	ENST00000407714.2	NP_005292.2
GPR35	NM_001195381.3	c.416C>T	p.Thr139Met	missense_variant	6/6		NP_001182310.1
GPR35	NM_001195382.3	c.416C>T	p.Thr139Met	missense_variant	6/6		NP_001182311.1
GPR35	NM_001394730.1	c.416C>T	p.Thr139Met	missense_variant	6/6		NP_001381659.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GPR35	ENST00000407714.2	c.323C>T	p.Thr108Met	missense_variant	2/2	1	NM_005301.5	ENSP00000384263.1

Frequencies

GnomAD3 genomes AF: 0.184 AC: 28056 AN: 152120 Hom.: 2685 Cov.: 33

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

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.: 44 AF XY: 0.171 AC XY: 119427 AN XY: 697364

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.: 33 AF XY: 0.183 AC XY: 13632 AN XY: 74426

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

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 18, 2020	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	T
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	N
LIST_S2	Benign	0.52	.;.;T;.;T
MetaRNN	Benign	0.0054	T;T;T;T;T
MetaSVM	Benign	-0.77	T
MutationAssessor	Benign	1.5	L;L;.;L;L
PrimateAI	Benign	0.45	T
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	T
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

Other links and lift over

dbSNP: rs3749171; hg19: chr2-241569692; COSMIC: COSV60576792;