dbSNP rs2480345: GPR158:p.Ala425Asp (chr10-25412412-C-A) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_020752.3(GPR158):c.1274C>A(p.Ala425Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,740 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. A425G) has been classified as Benign.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

GPR158
NM_020752.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.28

Publications

0 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: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GPR158	NM_020752.3 link	c.1274C>A	p.Ala425Asp	missense_variant	Exon 4 of 11	ENST00000376351.4	NP_065803.2	Q5T848
GPR158	XR_930512.4 link	n.1694C>A		non_coding_transcript_exon_variant	Exon 4 of 12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GPR158	ENST00000376351.4 link	c.1274C>A	p.Ala425Asp	missense_variant	Exon 4 of 11	1	NM_020752.3	ENSP00000365529.3		Q5T848
GPR158	ENST00000650135.1 link	c.1037C>A	p.Ala346Asp	missense_variant	Exon 5 of 12			ENSP00000498176.1		A0A3B3IUC3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461740

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727190

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:

33478

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1111872

Other (OTH)

AF:

0.00

AC:

AN:

60392

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), 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

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.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.80

BayesDel_addAF

Uncertain

0.11

BayesDel_noAF

Uncertain

-0.070

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.41

.;T

Eigen

Uncertain

0.50

Eigen_PC

Uncertain

0.51

FATHMM_MKL

Uncertain

0.90

LIST_S2

Uncertain

0.89

D;D

M_CAP

Benign

0.056

MetaRNN

Uncertain

0.69

D;D

MetaSVM

Uncertain

-0.22

MutationAssessor

Uncertain

2.2

.;M

PhyloP100

3.3

PrimateAI

Uncertain

0.58

PROVEAN

Uncertain

-3.9

.;D

REVEL

Uncertain

0.37

Sift

Uncertain

0.0070

.;D

Sift4G

Uncertain

0.0090

.;D

Polyphen

0.96

.;D

Vest4

0.70

MutPred

0.71

.;Loss of helix (P = 0.3949);

MVP

0.35

MPC

0.40

ClinPred

0.96

GERP RS

4.0

Varity_R

0.59

gMVP

0.87

Mutation Taster

=74/26

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over