2-240630029-A-T

Position:

• chr2-240630029-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_005301.5(GPR35):​c.77A>T​(p.Tyr26Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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 Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: GPR35 NM_005301.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.83

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.22944868).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GPR35	NM_005301.5	c.77A>T	p.Tyr26Phe	missense_variant	2/2	ENST00000407714.2	NP_005292.2
GPR35	NM_001195381.3	c.170A>T	p.Tyr57Phe	missense_variant	6/6		NP_001182310.1
GPR35	NM_001195382.3	c.170A>T	p.Tyr57Phe	missense_variant	6/6		NP_001182311.1
GPR35	NM_001394730.1	c.170A>T	p.Tyr57Phe	missense_variant	6/6		NP_001381659.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GPR35	ENST00000407714.2	c.77A>T	p.Tyr26Phe	missense_variant	2/2	1	NM_005301.5	ENSP00000384263.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 04, 2023

The c.170A>T (p.Y57F) alteration is located in exon 6 (coding exon 2) of the GPR35 gene. This alteration results from a A to T substitution at nucleotide position 170, causing the tyrosine (Y) at amino acid position 57 to be replaced by a phenylalanine (F). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	15
DANN	Benign	0.87
DEOGEN2	Benign	0.015	T;T;.;T;T
Eigen	Benign	-0.057
Eigen_PC	Benign	-0.15
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Benign	0.56	.;.;T;.;T
M_CAP	Benign	0.0098	T
MetaRNN	Benign	0.23	T;T;T;T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	1.1	L;L;.;L;L
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-1.3	N;N;.;N;.
REVEL	Benign	0.13
Sift	Benign	0.26	T;T;.;T;.
Sift4G	Benign	0.12	T;T;T;T;T
Polyphen		1.0	D;D;.;D;D
Vest4		0.41
MutPred		0.37		Loss of catalytic residue at L21 (P = 0.0487);Loss of catalytic residue at L21 (P = 0.0487);.;Loss of catalytic residue at L21 (P = 0.0487);Loss of catalytic residue at L21 (P = 0.0487);
MVP		0.11
MPC		0.30
ClinPred		0.35	T
GERP RS		3.6
Varity_R		0.067
gMVP		0.14

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr2-241569446;