2-240630227-C-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.275C>T(p.Ser92Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000707 in 1,415,136 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 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)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: GPR35 NM_005301.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.0690

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=0.23317406).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GPR35	NM_005301.5	c.275C>T	p.Ser92Phe	missense_variant	2/2	ENST00000407714.2
GPR35	NM_001195381.3	c.368C>T	p.Ser123Phe	missense_variant	6/6
GPR35	NM_001195382.3	c.368C>T	p.Ser123Phe	missense_variant	6/6
GPR35	NM_001394730.1	c.368C>T	p.Ser123Phe	missense_variant	6/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GPR35	ENST00000407714.2	c.275C>T	p.Ser92Phe	missense_variant	2/2	1	NM_005301.5	P2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.07e-7 AC: 1 AN: 1415136 Hom.: 0 Cov.: 34 AF XY: 0.00000143 AC XY: 1 AN XY: 698860

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000255

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

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

Jun 07, 2023

The c.368C>T (p.S123F) alteration is located in exon 6 (coding exon 2) of the GPR35 gene. This alteration results from a C to T substitution at nucleotide position 368, causing the serine (S) at amino acid position 123 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	Uncertain	0.51
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Benign	-0.38
Cadd	Benign	23
Dann	Uncertain	1.0
DEOGEN2	Benign	0.019	T;T;.;T;T
Eigen	Benign	-0.042
Eigen_PC	Benign	-0.20
FATHMM_MKL	Benign	0.020	N
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.23	T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.3	M;M;.;M;M
MutationTaster	Benign	1.0	N;N;N;N;N
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-1.8	N;N;.;N;.
REVEL	Benign	0.20
Sift	Benign	0.053	T;T;.;T;.
Sift4G	Benign	0.12	T;T;T;T;T
Polyphen		0.99	D;D;.;D;D
Vest4		0.25
MutPred		0.53		Gain of catalytic residue at S92 (P = 0.0208);Gain of catalytic residue at S92 (P = 0.0208);.;Gain of catalytic residue at S92 (P = 0.0208);Gain of catalytic residue at S92 (P = 0.0208);
MVP		0.38
MPC		0.97
ClinPred		0.69	D
GERP RS		2.2
Varity_R		0.23
gMVP		0.47

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1289052148; hg19: chr2-241569644;