chr2-240630037-G-A

Position:

• chr2-240630037-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.85G>A​(p.Val29Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00921 in 1,612,702 control chromosomes in the GnomAD database, including 104 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 0.0065 (7 hom., cov: 33)
  • Exomes 𝑓: 0.0095 (97 hom.)
• Consequence: GPR35 NM_005301.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -7.32

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=0.0038455725).
• BP6: Variant 2-240630037-G-A is Benign according to our data. Variant chr2-240630037-G-A is described in ClinVar as [Benign]. Clinvar id is 784590.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd4 at 7 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GPR35	NM_005301.5	c.85G>A	p.Val29Ile	missense_variant	2/2	ENST00000407714.2	NP_005292.2
GPR35	NM_001195381.3	c.178G>A	p.Val60Ile	missense_variant	6/6		NP_001182310.1
GPR35	NM_001195382.3	c.178G>A	p.Val60Ile	missense_variant	6/6		NP_001182311.1
GPR35	NM_001394730.1	c.178G>A	p.Val60Ile	missense_variant	6/6		NP_001381659.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GPR35	ENST00000407714.2	c.85G>A	p.Val29Ile	missense_variant	2/2	1	NM_005301.5	ENSP00000384263.1

Frequencies

GnomAD3 genomes AF: 0.00648 AC: 986 AN: 152200 Hom.: 7 Cov.: 33

Gnomad AFR AF: 0.00174

Gnomad AMI AF: 0.0121

Gnomad AMR AF: 0.00536

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0104

Gnomad FIN AF: 0.00405

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0104

Gnomad OTH AF: 0.00861

GnomAD3 exomes AF: 0.00765 AC: 1916 AN: 250360 Hom.: 15 AF XY: 0.00803 AC XY: 1088 AN XY: 135554

Gnomad AFR exome AF: 0.00148

Gnomad AMR exome AF: 0.00596

Gnomad ASJ exome AF: 0.000698

Gnomad EAS exome AF: 0.000163

Gnomad SAS exome AF: 0.00967

Gnomad FIN exome AF: 0.00453

Gnomad NFE exome AF: 0.0109

Gnomad OTH exome AF: 0.00801

GnomAD4 exome AF: 0.00950 AC: 13876 AN: 1460384 Hom.: 97 Cov.: 33 AF XY: 0.00957 AC XY: 6950 AN XY: 726560

Gnomad4 AFR exome AF: 0.00158

Gnomad4 AMR exome AF: 0.00599

Gnomad4 ASJ exome AF: 0.000153

Gnomad4 EAS exome AF: 0.000176

Gnomad4 SAS exome AF: 0.00934

Gnomad4 FIN exome AF: 0.00476

Gnomad4 NFE exome AF: 0.0107

Gnomad4 OTH exome AF: 0.00911

GnomAD4 genome AF: 0.00647 AC: 985 AN: 152318 Hom.: 7 Cov.: 33 AF XY: 0.00623 AC XY: 464 AN XY: 74486

Gnomad4 AFR AF: 0.00173

Gnomad4 AMR AF: 0.00536

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0104

Gnomad4 FIN AF: 0.00405

Gnomad4 NFE AF: 0.0104

Gnomad4 OTH AF: 0.00852

Alfa AF: 0.00960 Hom.: 8

Bravo AF: 0.00606

TwinsUK AF: 0.0102 AC: 38

ALSPAC AF: 0.00727 AC: 28

ESP6500AA AF: 0.00204 AC: 9

ESP6500EA AF: 0.0122 AC: 105

ExAC AF: 0.00777 AC: 943

Asia WGS AF: 0.00404 AC: 14 AN: 3478

EpiCase AF: 0.0112

EpiControl AF: 0.0104

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

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.083
BayesDel_addAF	Benign	-0.70	T
BayesDel_noAF	Benign	-0.76
CADD	Benign	0.0010
DANN	Benign	0.41
DEOGEN2	Benign	0.0074	T;T;.;T;T
Eigen	Benign	-2.1
Eigen_PC	Benign	-2.2
FATHMM_MKL	Benign	0.022	N
LIST_S2	Benign	0.30	.;.;T;.;T
MetaRNN	Benign	0.0038	T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.55	N;N;.;N;N
PrimateAI	Benign	0.34	T
PROVEAN	Benign	0.030	N;N;.;N;.
REVEL	Benign	0.0020
Sift	Benign	1.0	T;T;.;T;.
Sift4G	Benign	0.83	T;T;T;T;T
Polyphen		0.0	B;B;.;B;B
Vest4		0.062
MVP		0.040
MPC		0.23
ClinPred		0.010	T
GERP RS		-7.6
Varity_R		0.024
gMVP		0.029

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: rs139197368; hg19: chr2-241569454;