dbSNP rs10828833: GPR158:p.Ile1209Leu (chr10-25599251-A-C) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_020752.3(GPR158):c.3625A>C(p.Ile1209Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000206 in 1,459,000 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

GPR158
NM_020752.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.874

Publications

29 publications found

Variant links:

Genes affected

GPR158 (HGNC:23689): (G protein-coupled receptor 158) Predicted to enable G protein-coupled receptor activity. Predicted to act upstream of or within G protein-coupled receptor signaling pathway and protein localization to plasma membrane. Predicted to be located in membrane. [provided by Alliance of Genome Resources, Apr 2022]

GPR158 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.05867046).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020752.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GPR158	NM_020752.3	MANE Select	c.3625A>C	p.Ile1209Leu	missense	Exon 11 of 11	NP_065803.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
GPR158	ENST00000376351.4	TSL:1 MANE Select	c.3625A>C	p.Ile1209Leu	missense	Exon 11 of 11	ENSP00000365529.3
GPR158	ENST00000490549.1	TSL:1	n.1812A>C		non_coding_transcript_exon	Exon 3 of 3
GPR158	ENST00000650135.1		c.3388A>C	p.Ile1130Leu	missense	Exon 12 of 12	ENSP00000498176.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000206

AC:

AN:

1459000

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

725966

show subpopulations

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

African (AFR)

AF:

0.0000598

AC:

AN:

33432

American (AMR)

AF:

0.00

AC:

AN:

44692

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26088

East Asian (EAS)

AF:

0.00

AC:

AN:

39684

South Asian (SAS)

AF:

0.00

AC:

AN:

86198

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51906

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5760

European-Non Finnish (NFE)

AF:

9.00e-7

AC:

AN:

1110914

Other (OTH)

AF:

0.00

AC:

AN:

60326

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.225

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

59829

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.081

BayesDel_addAF

Benign

-0.27

BayesDel_noAF

Benign

-0.63

CADD

Benign

7.8

(source)

DANN

Benign

0.88

DEOGEN2

Benign

0.0079

Eigen

Benign

-0.81

Eigen_PC

Benign

-0.66

FATHMM_MKL

Uncertain

0.82

LIST_S2

Benign

0.17

M_CAP

Benign

0.014

MetaRNN

Benign

0.059

MetaSVM

Benign

-0.99

MutationAssessor

Benign

0.34

PhyloP100

0.87

PrimateAI

Benign

0.26

PROVEAN

Benign

0.17

REVEL

Benign

0.078

Sift

Benign

0.058

Sift4G

Benign

0.15

Polyphen

0.0020

Vest4

0.12

MutPred

0.14

Loss of ubiquitination at K1214 (P = 0.0801)

MVP

0.17

MPC

0.094

ClinPred

0.038

GERP RS

3.1

Varity_R

0.057

gMVP

0.052

Mutation Taster

=98/2

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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over