NM_005301.5:c.880A>T

Variant names:

• chr2-240630832-A-T
• rs3749172
• NM_005301.5:c.880A>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.880A>T​(p.Ser294Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000558 in 1,612,878 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. S294R) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000060 (0 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 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=0.14017478).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GPR35	NM_005301.5	c.880A>T	p.Ser294Cys	missense_variant	Exon 2 of 2	ENST00000407714.2	NP_005292.2
GPR35	NM_001195381.3	c.973A>T	p.Ser325Cys	missense_variant	Exon 6 of 6		NP_001182310.1
GPR35	NM_001195382.3	c.973A>T	p.Ser325Cys	missense_variant	Exon 6 of 6		NP_001182311.1
GPR35	NM_001394730.1	c.973A>T	p.Ser325Cys	missense_variant	Exon 6 of 6		NP_001381659.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GPR35	ENST00000407714.2	c.880A>T	p.Ser294Cys	missense_variant	Exon 2 of 2	1	NM_005301.5	ENSP00000384263.1

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152026 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000199 AC: 5 AN: 250952 Hom.: 0 AF XY: 0.0000221 AC XY: 3 AN XY: 135756

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000353

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000596 AC: 87 AN: 1460852 Hom.: 0 Cov.: 66 AF XY: 0.0000633 AC XY: 46 AN XY: 726728

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000701

Gnomad4 OTH exome AF: 0.000132

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152026 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74246

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00

ExAC AF: 0.0000165 AC: 2

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.091
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	7.6
DANN	Benign	0.79
DEOGEN2	Benign	0.014	T;T;.;T;T
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.040	N
LIST_S2	Benign	0.31	.;.;T;.;T
M_CAP	Benign	0.040	D
MetaRNN	Benign	0.14	T;T;T;T;T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	0.55	N;N;.;N;N
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-1.1	N;N;.;N;.
REVEL	Benign	0.067
Sift	Benign	0.037	D;D;.;D;.
Sift4G	Uncertain	0.045	D;D;T;D;D
Polyphen		0.80	P;P;.;P;P
Vest4		0.18
MutPred		0.35		Loss of disorder (P = 0.0016);Loss of disorder (P = 0.0016);.;Loss of disorder (P = 0.0016);Loss of disorder (P = 0.0016);
MVP		0.51
MPC		0.79
ClinPred		0.13	T
GERP RS		-3.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.076
gMVP		0.15

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;