2-240630328-G-A

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_005301.5(GPR35):c.376G>A(p.Gly126Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0078 in 1,594,464 control chromosomes in the GnomAD database, including 72 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 (★★).

• Frequency:
  • Genomes: 𝑓 0.0057 (5 hom., cov: 33)
  • Exomes 𝑓: 0.0080 (67 hom.)
• Consequence: GPR35 NM_005301.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.563

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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.007158071).
• BP6: Variant 2-240630328-G-A is Benign according to our data. Variant chr2-240630328-G-A is described in ClinVar as [Benign]. Clinvar id is 773436.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GPR35	NM_005301.5	c.376G>A	p.Gly126Arg	missense_variant	2/2	ENST00000407714.2
GPR35	NM_001195381.3	c.469G>A	p.Gly157Arg	missense_variant	6/6
GPR35	NM_001195382.3	c.469G>A	p.Gly157Arg	missense_variant	6/6
GPR35	NM_001394730.1	c.469G>A	p.Gly157Arg	missense_variant	6/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GPR35	ENST00000407714.2	c.376G>A	p.Gly126Arg	missense_variant	2/2	1	NM_005301.5	P2

Frequencies

GnomAD3 genomes AF: 0.00574 AC: 874 AN: 152210 Hom.: 5 Cov.: 33

Gnomad AFR AF: 0.00125

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00327

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0101

Gnomad FIN AF: 0.00555

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00961

Gnomad OTH AF: 0.00335

GnomAD3 exomes AF: 0.00644 AC: 1485 AN: 230422 Hom.: 12 AF XY: 0.00694 AC XY: 880 AN XY: 126808

Gnomad AFR exome AF: 0.00129

Gnomad AMR exome AF: 0.00156

Gnomad ASJ exome AF: 0.000317

Gnomad EAS exome AF: 0.0000562

Gnomad SAS exome AF: 0.0120

Gnomad FIN exome AF: 0.00646

Gnomad NFE exome AF: 0.00882

Gnomad OTH exome AF: 0.00638

GnomAD4 exome AF: 0.00802 AC: 11571 AN: 1442136 Hom.: 67 Cov.: 40 AF XY: 0.00806 AC XY: 5772 AN XY: 716312

Gnomad4 AFR exome AF: 0.000874

Gnomad4 AMR exome AF: 0.00158

Gnomad4 ASJ exome AF: 0.000426

Gnomad4 EAS exome AF: 0.0000253

Gnomad4 SAS exome AF: 0.0114

Gnomad4 FIN exome AF: 0.00668

Gnomad4 NFE exome AF: 0.00889

Gnomad4 OTH exome AF: 0.00610

GnomAD4 genome AF: 0.00573 AC: 873 AN: 152328 Hom.: 5 Cov.: 33 AF XY: 0.00563 AC XY: 419 AN XY: 74486

Gnomad4 AFR AF: 0.00125

Gnomad4 AMR AF: 0.00327

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00994

Gnomad4 FIN AF: 0.00555

Gnomad4 NFE AF: 0.00961

Gnomad4 OTH AF: 0.00331

Alfa AF: 0.00393 Hom.: 0

Bravo AF: 0.00469

TwinsUK AF: 0.00836 AC: 31

ALSPAC AF: 0.00908 AC: 35

ESP6500AA AF: 0.000685 AC: 3

ESP6500EA AF: 0.00901 AC: 77

ExAC AF: 0.00669 AC: 800

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	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2023	GPR35: BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	Invitae	Dec 31, 2019	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.68	T
BayesDel_noAF	Benign	-0.74
Cadd	Benign	0.81
Dann	Benign	0.61
DEOGEN2	Benign	0.0055	T;T;.;T;T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.0099	N
MetaRNN	Benign	0.0072	T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.33	N;N;.;N;N
MutationTaster	Benign	1.0	N;N;N;N;N
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	0.39	N;N;.;N;.
REVEL	Benign	0.0060
Sift	Benign	0.54	T;T;.;T;.
Sift4G	Benign	0.53	T;T;T;T;T
Polyphen		0.015	B;B;.;B;B
Vest4		0.062
MutPred		0.38		Gain of methylation at G126 (P = 0.0101);Gain of methylation at G126 (P = 0.0101);.;Gain of methylation at G126 (P = 0.0101);Gain of methylation at G126 (P = 0.0101);
MVP		0.11
MPC		0.34
ClinPred		0.0014	T
GERP RS		-1.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.0
Varity_R		0.060
gMVP		0.23

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: rs61734453; hg19: chr2-241569745;