chr2-240630227-C-T

Variant names:

• chr2-240630227-C-T
• rs1289052148
• NM_005301.5:c.275C>T

Variant summary

Our verdict is Uncertain significance. The variant received 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. 13/22 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
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.23317406).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005301.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GPR35	NM_005301.5	MANE Select	c.275C>T	p.Ser92Phe	missense	Exon 2 of 2	NP_005292.2
	GPR35	NM_001195381.3		c.368C>T	p.Ser123Phe	missense	Exon 6 of 6	NP_001182310.1	Q9HC97-2
	GPR35	NM_001195382.3		c.368C>T	p.Ser123Phe	missense	Exon 6 of 6	NP_001182311.1	Q9HC97-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GPR35	ENST00000407714.2	TSL:1 MANE Select	c.275C>T	p.Ser92Phe	missense	Exon 2 of 2	ENSP00000384263.1	Q9HC97-1
	GPR35	ENST00000430267.2	TSL:5	c.368C>T	p.Ser123Phe	missense	Exon 2 of 2	ENSP00000411788.2	Q9HC97-2
	GPR35	ENST00000319838.10	TSL:2	c.275C>T	p.Ser92Phe	missense	Exon 6 of 6	ENSP00000322731.5	Q9HC97-1

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

African (AFR) AF: 0.00 AC: 0 AN: 32996

American (AMR) AF: 0.00 AC: 0 AN: 43430

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24140

East Asian (EAS) AF: 0.0000255 AC: 1 AN: 39152

South Asian (SAS) AF: 0.00 AC: 0 AN: 81660

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 38368

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5618

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1090998

Other (OTH) AF: 0.00 AC: 0 AN: 58774

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Benign	-0.042
Eigen_PC	Benign	-0.20
FATHMM_MKL	Benign	0.020	N
LIST_S2	Benign	0.78	T
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.23	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		-0.069
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-1.8	N
REVEL	Benign	0.20
Sift	Benign	0.053	T
Sift4G	Benign	0.12	T
Polyphen		0.99	D
Vest4		0.25
MutPred		0.53		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
Mutation Taster		=93/7	polymorphism

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

Other links and lift over

dbSNP: rs1289052148; hg19: chr2-241569644;