2-240630275-C-T

Variant names:

• chr2-240630275-C-T
• rs3749171
• NM_005301.5:c.323C>T

Variant summary

Our verdict is Benign. The variant received -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. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• 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
• Publications: 84 publications found

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

Our verdict: Benign. The variant received -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 VariationId 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	c.323C>T	p.Thr108Met	missense_variant	Exon 2 of 2	ENST00000407714.2	NP_005292.2
GPR35	NM_001195381.3	c.416C>T	p.Thr139Met	missense_variant	Exon 6 of 6		NP_001182310.1
GPR35	NM_001195382.3	c.416C>T	p.Thr139Met	missense_variant	Exon 6 of 6		NP_001182311.1
GPR35	NM_001394730.1	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	c.323C>T	p.Thr108Met	missense_variant	Exon 2 of 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

GnomAD2 exomes AF: 0.164 AC: 34813 AN: 212636 AF XY: 0.160

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 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

African (AFR) AF: 0.218 AC: 7137 AN: 32786

American (AMR) AF: 0.127 AC: 5407 AN: 42458

Ashkenazi Jewish (ASJ) AF: 0.123 AC: 2907 AN: 23662

East Asian (EAS) AF: 0.0723 AC: 2833 AN: 39176

South Asian (SAS) AF: 0.113 AC: 9050 AN: 80344

European-Finnish (FIN) AF: 0.249 AC: 9474 AN: 38026

Middle Eastern (MID) AF: 0.0985 AC: 550 AN: 5582

European-Non Finnish (NFE) AF: 0.182 AC: 198570 AN: 1091096

Other (OTH) AF: 0.165 AC: 9650 AN: 58606

GnomAD4 genome AF: 0.184 AC: 28063 AN: 152238 Hom.: 2689 Cov.: 33 AF XY: 0.183 AC XY: 13632 AN XY: 74426

African (AFR) AF: 0.222 AC: 9228 AN: 41548

American (AMR) AF: 0.145 AC: 2224 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.115 AC: 399 AN: 3472

East Asian (EAS) AF: 0.0774 AC: 401 AN: 5180

South Asian (SAS) AF: 0.114 AC: 550 AN: 4826

European-Finnish (FIN) AF: 0.252 AC: 2675 AN: 10606

Middle Eastern (MID) AF: 0.110 AC: 32 AN: 292

European-Non Finnish (NFE) AF: 0.177 AC: 12064 AN: 67988

Other (OTH) AF: 0.145 AC: 307 AN: 2114

Alfa AF: 0.176 Hom.: 6222

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

-

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	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
PhyloP100		-0.80
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
Mutation Taster		=100/0	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: rs3749171; hg19: chr2-241569692; COSMIC: COSV60576792;