chr2-240630025-G-A

Position:

• chr2-240630025-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.73G>A​(p.Ala25Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0127 in 1,612,806 control chromosomes in the GnomAD database, including 163 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 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 0.0094 (9 hom., cov: 33)
  • Exomes 𝑓: 0.013 (154 hom.)
• Consequence: GPR35 NM_005301.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.59

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=0.0048702955).
• BP6: Variant 2-240630025-G-A is Benign according to our data. Variant chr2-240630025-G-A is described in ClinVar as [Benign]. Clinvar id is 777143.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd4 at 9 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GPR35	NM_005301.5	c.73G>A	p.Ala25Thr	missense_variant	2/2	ENST00000407714.2	NP_005292.2
GPR35	NM_001195381.3	c.166G>A	p.Ala56Thr	missense_variant	6/6		NP_001182310.1
GPR35	NM_001195382.3	c.166G>A	p.Ala56Thr	missense_variant	6/6		NP_001182311.1
GPR35	NM_001394730.1	c.166G>A	p.Ala56Thr	missense_variant	6/6		NP_001381659.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GPR35	ENST00000407714.2	c.73G>A	p.Ala25Thr	missense_variant	2/2	1	NM_005301.5	ENSP00000384263.1

Frequencies

GnomAD3 genomes AF: 0.00939 AC: 1429 AN: 152196 Hom.: 9 Cov.: 33

Gnomad AFR AF: 0.00253

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00458

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00373

Gnomad FIN AF: 0.0192

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0148

Gnomad OTH AF: 0.00718

GnomAD3 exomes AF: 0.00970 AC: 2431 AN: 250522 Hom.: 21 AF XY: 0.00987 AC XY: 1339 AN XY: 135598

Gnomad AFR exome AF: 0.00210

Gnomad AMR exome AF: 0.00333

Gnomad ASJ exome AF: 0.00458

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00539

Gnomad FIN exome AF: 0.0165

Gnomad NFE exome AF: 0.0145

Gnomad OTH exome AF: 0.0116

GnomAD4 exome AF: 0.0130 AC: 19027 AN: 1460492 Hom.: 154 Cov.: 33 AF XY: 0.0129 AC XY: 9358 AN XY: 726576

Gnomad4 AFR exome AF: 0.00200

Gnomad4 AMR exome AF: 0.00342

Gnomad4 ASJ exome AF: 0.00421

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.00575

Gnomad4 FIN exome AF: 0.0178

Gnomad4 NFE exome AF: 0.0148

Gnomad4 OTH exome AF: 0.0126

GnomAD4 genome AF: 0.00938 AC: 1428 AN: 152314 Hom.: 9 Cov.: 33 AF XY: 0.00936 AC XY: 697 AN XY: 74480

Gnomad4 AFR AF: 0.00253

Gnomad4 AMR AF: 0.00457

Gnomad4 ASJ AF: 0.00202

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00373

Gnomad4 FIN AF: 0.0192

Gnomad4 NFE AF: 0.0148

Gnomad4 OTH AF: 0.00711

Alfa AF: 0.0112 Hom.: 16

Bravo AF: 0.00778

TwinsUK AF: 0.0154 AC: 57

ALSPAC AF: 0.0148 AC: 57

ESP6500AA AF: 0.00340 AC: 15

ESP6500EA AF: 0.0120 AC: 103

ExAC AF: 0.00988 AC: 1199

Asia WGS AF: 0.00318 AC: 12 AN: 3478

EpiCase AF: 0.0112

EpiControl AF: 0.0113

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2023	GPR35: BP4, BS1, BS2 -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 31, 2019	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.088
BayesDel_addAF	Benign	-0.70	T
BayesDel_noAF	Benign	-0.76
CADD	Benign	0.016
DANN	Benign	0.52
DEOGEN2	Benign	0.0072	T;T;.;T;T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.042	N
LIST_S2	Benign	0.34	.;.;T;.;T
MetaRNN	Benign	0.0049	T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.34	N;N;.;N;N
PrimateAI	Benign	0.27	T
PROVEAN	Benign	0.060	N;N;.;N;.
REVEL	Benign	0.024
Sift	Benign	0.35	T;T;.;T;.
Sift4G	Benign	0.28	T;T;T;T;T
Polyphen		0.052	B;B;.;B;B
Vest4		0.025
MVP		0.081
MPC		0.28
ClinPred		0.00091	T
GERP RS		-2.8
Varity_R		0.023
gMVP		0.064

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: rs35146537; hg19: chr2-241569442;