dbSNP rs527604027: GPR35:p.Thr86Lys (chr2-240630209-C-A) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_005301.5(GPR35):c.257C>A(p.Thr86Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000281 in 1,421,904 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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. T86M) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000028 ( 0 hom. )

Consequence

GPR35
NM_005301.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.0720

Publications

0 publications found

Variant links:

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]

GPR35 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.33339375).

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
GPR35	NM_005301.5	MANE Select	c.257C>A	p.Thr86Lys	missense	Exon 2 of 2	NP_005292.2
GPR35	NM_001195381.3		c.350C>A	p.Thr117Lys	missense	Exon 6 of 6	NP_001182310.1	Q9HC97-2
GPR35	NM_001195382.3		c.350C>A	p.Thr117Lys	missense	Exon 6 of 6	NP_001182311.1	Q9HC97-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
GPR35	ENST00000407714.2	TSL:1 MANE Select	c.257C>A	p.Thr86Lys	missense	Exon 2 of 2	ENSP00000384263.1	Q9HC97-1
GPR35	ENST00000430267.2	TSL:5	c.350C>A	p.Thr117Lys	missense	Exon 2 of 2	ENSP00000411788.2	Q9HC97-2
GPR35	ENST00000319838.10	TSL:2	c.257C>A	p.Thr86Lys	missense	Exon 6 of 6	ENSP00000322731.5	Q9HC97-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000281

AC:

AN:

1421904

Hom.:

Cov.:

AF XY:

0.00000427

AC XY:

AN XY:

703022

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

33078

American (AMR)

AF:

0.00

AC:

AN:

43796

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24828

East Asian (EAS)

AF:

0.00

AC:

AN:

39166

South Asian (SAS)

AF:

0.0000240

AC:

AN:

83440

European-Finnish (FIN)

AF:

0.00

AC:

AN:

39062

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5648

European-Non Finnish (NFE)

AF:

0.00000183

AC:

AN:

1093862

Other (OTH)

AF:

0.00

AC:

AN:

59024

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000101728), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.275

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.27

BayesDel_addAF

Benign

-0.035

BayesDel_noAF

Benign

-0.29

CADD

Benign

(source)

DANN

Benign

0.94

DEOGEN2

Benign

0.015

Eigen

Benign

-0.28

Eigen_PC

Benign

-0.45

FATHMM_MKL

Benign

0.061

LIST_S2

Benign

0.52

M_CAP

Benign

0.058

MetaRNN

Benign

0.33

MetaSVM

Benign

-0.78

MutationAssessor

Uncertain

2.0

PhyloP100

-0.072

PrimateAI

Benign

0.26

PROVEAN

Benign

-1.2

REVEL

Uncertain

0.35

Sift

Benign

0.10

Sift4G

Benign

0.91

Polyphen

0.99

Vest4

0.28

MutPred

0.62

Gain of methylation at T86 (P = 0.0123)

MVP

0.81

MPC

0.84

ClinPred

0.37

GERP RS

3.1

Varity_R

0.10

gMVP

0.33

Mutation Taster

=89/11

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over