rs3749172

chr2-240630832-A-Cchr2-240630832-A-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_005301.5(GPR35):c.880A>C(p.Ser294Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.565 in 1,612,842 control chromosomes in the GnomAD database, including 265,508 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S294N) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.47 (19054 hom., cov: 33)
  • Exomes 𝑓: 0.57 (246454 hom.)
• Consequence: GPR35 NM_005301.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.16

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.4194889E-6).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.762 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GPR35	NM_005301.5	c.880A>C	p.Ser294Arg	missense_variant	2/2	ENST00000407714.2
GPR35	NM_001195381.3	c.973A>C	p.Ser325Arg	missense_variant	6/6
GPR35	NM_001195382.3	c.973A>C	p.Ser325Arg	missense_variant	6/6
GPR35	NM_001394730.1	c.973A>C	p.Ser325Arg	missense_variant	6/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GPR35	ENST00000407714.2	c.880A>C	p.Ser294Arg	missense_variant	2/2	1	NM_005301.5	P2

Frequencies

GnomAD3 genomes AF: 0.475 AC: 72152 AN: 151968 Hom.: 19036 Cov.: 33

Gnomad AFR AF: 0.248

Gnomad AMI AF: 0.536

Gnomad AMR AF: 0.395

Gnomad ASJ AF: 0.486

Gnomad EAS AF: 0.699

Gnomad SAS AF: 0.783

Gnomad FIN AF: 0.584

Gnomad MID AF: 0.509

Gnomad NFE AF: 0.573

Gnomad OTH AF: 0.481

GnomAD3 exomes AF: 0.555 AC: 139371 AN: 250952 Hom.: 41070 AF XY: 0.578 AC XY: 78475 AN XY: 135756

Gnomad AFR exome AF: 0.241

Gnomad AMR exome AF: 0.394

Gnomad ASJ exome AF: 0.481

Gnomad EAS exome AF: 0.703

Gnomad SAS exome AF: 0.778

Gnomad FIN exome AF: 0.586

Gnomad NFE exome AF: 0.567

Gnomad OTH exome AF: 0.537

GnomAD4 exome AF: 0.574 AC: 838815 AN: 1460756 Hom.: 246454 Cov.: 66 AF XY: 0.582 AC XY: 423113 AN XY: 726690

Gnomad4 AFR exome AF: 0.246

Gnomad4 AMR exome AF: 0.391

Gnomad4 ASJ exome AF: 0.483

Gnomad4 EAS exome AF: 0.711

Gnomad4 SAS exome AF: 0.776

Gnomad4 FIN exome AF: 0.585

Gnomad4 NFE exome AF: 0.573

Gnomad4 OTH exome AF: 0.563

GnomAD4 genome AF: 0.475 AC: 72187 AN: 152086 Hom.: 19054 Cov.: 33 AF XY: 0.480 AC XY: 35678 AN XY: 74344

Gnomad4 AFR AF: 0.248

Gnomad4 AMR AF: 0.395

Gnomad4 ASJ AF: 0.486

Gnomad4 EAS AF: 0.700

Gnomad4 SAS AF: 0.782

Gnomad4 FIN AF: 0.584

Gnomad4 NFE AF: 0.573

Gnomad4 OTH AF: 0.486

Alfa AF: 0.540 Hom.: 31015

Bravo AF: 0.445

TwinsUK AF: 0.576 AC: 2136

ALSPAC AF: 0.589 AC: 2269

ESP6500AA AF: 0.247 AC: 1088

ESP6500EA AF: 0.565 AC: 4857

ExAC AF: 0.559 AC: 67823

Asia WGS AF: 0.712 AC: 2474 AN: 3476

EpiCase AF: 0.563

EpiControl AF: 0.562

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.72	T
BayesDel_noAF	Benign	-0.66
Cadd	Benign	2.3
Dann	Benign	0.22
DEOGEN2	Benign	0.0055	T;T;.;T;T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.026	N
MetaRNN	Benign	0.0000014	T;T;T;T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	0.20	N;N;.;N;N
MutationTaster	Benign	1.0	P;P;P;P;P
PrimateAI	Benign	0.28	T
PROVEAN	Benign	1.3	N;N;.;N;.
REVEL	Benign	0.060
Sift	Benign	0.66	T;T;.;T;.
Sift4G	Benign	0.55	T;T;T;T;T
Polyphen		0.0	B;B;.;B;B
Vest4		0.045
MutPred		0.11		Loss of ubiquitination at K299 (P = 0.0283);Loss of ubiquitination at K299 (P = 0.0283);.;Loss of ubiquitination at K299 (P = 0.0283);Loss of ubiquitination at K299 (P = 0.0283);
MPC		0.31
ClinPred		0.0013	T
GERP RS		-3.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.053
gMVP		0.18

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: rs3749172; hg19: chr2-241570249; COSMIC: COSV60576322;