Genetic Variant GPR158:p.Ala425Gly (chr10-25412412-C-G) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_020752.3(GPR158):c.1274C>G(p.Ala425Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.684 in 1,612,848 control chromosomes in the GnomAD database, including 389,197 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.60 ( 29420 hom., cov: 33)

Exomes 𝑓: 0.69 ( 359777 hom. )

Consequence

GPR158
NM_020752.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 3.28

Publications

33 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=1.6245707E-6).

BP6

Variant 10-25412412-C-G is Benign according to our data. Variant chr10-25412412-C-G is described in ClinVar as Benign. ClinVar VariationId is 1294578.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.723 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GPR158	NM_020752.3 link	c.1274C>G	p.Ala425Gly	missense_variant	Exon 4 of 11	ENST00000376351.4	NP_065803.2	Q5T848
GPR158	XR_930512.4 link	n.1694C>G		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>G	p.Ala425Gly	missense_variant	Exon 4 of 11	1	NM_020752.3	ENSP00000365529.3		Q5T848
GPR158	ENST00000650135.1 link	c.1037C>G	p.Ala346Gly	missense_variant	Exon 5 of 12			ENSP00000498176.1		A0A3B3IUC3

Frequencies

GnomAD3 genomes

AF:

0.605

AC:

91930

AN:

151926

Hom.:

29412

Cov.:

show subpopulations

Gnomad AFR

AF:

0.470

Gnomad AMI

AF:

0.697

Gnomad AMR

AF:

0.545

Gnomad ASJ

AF:

0.681

Gnomad EAS

AF:

0.154

Gnomad SAS

AF:

0.646

Gnomad FIN

AF:

0.591

Gnomad MID

AF:

0.652

Gnomad NFE

AF:

0.728

Gnomad OTH

AF:

0.620

GnomAD2 exomes

AF:

0.611

AC:

153512

AN:

251442

AF XY:

0.627

show subpopulations

Gnomad AFR exome

AF:

0.459

Gnomad AMR exome

AF:

0.459

Gnomad ASJ exome

AF:

0.687

Gnomad EAS exome

AF:

0.148

Gnomad FIN exome

AF:

0.600

Gnomad NFE exome

AF:

0.732

Gnomad OTH exome

AF:

0.642

GnomAD4 exome

AF:

0.692

AC:

1010467

AN:

1460804

Hom.:

359777

Cov.:

AF XY:

0.693

AC XY:

503742

AN XY:

726776

show subpopulations

African (AFR)

AF:

0.456

AC:

15258

AN:

33462

American (AMR)

AF:

0.469

AC:

20955

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.685

AC:

17890

AN:

26120

East Asian (EAS)

AF:

0.130

AC:

5166

AN:

39700

South Asian (SAS)

AF:

0.667

AC:

57515

AN:

86232

European-Finnish (FIN)

AF:

0.607

AC:

32427

AN:

53414

Middle Eastern (MID)

AF:

0.651

AC:

3749

AN:

5762

European-Non Finnish (NFE)

AF:

0.736

AC:

817709

AN:

1111036

Other (OTH)

AF:

0.659

AC:

39798

AN:

60356

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.456

Heterozygous variant carriers

16107

32214

48320

64427

80534

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

19804

39608

59412

79216

99020

<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

AF:

0.605

AC:

91971

AN:

152044

Hom.:

29420

Cov.:

AF XY:

0.593

AC XY:

44027

AN XY:

74294

show subpopulations

African (AFR)

AF:

0.469

AC:

19461

AN:

41456

American (AMR)

AF:

0.545

AC:

8330

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.681

AC:

2366

AN:

3472

East Asian (EAS)

AF:

0.154

AC:

796

AN:

5172

South Asian (SAS)

AF:

0.647

AC:

3114

AN:

4816

European-Finnish (FIN)

AF:

0.591

AC:

6248

AN:

10564

Middle Eastern (MID)

AF:

0.660

AC:

194

AN:

294

European-Non Finnish (NFE)

AF:

0.728

AC:

49520

AN:

67978

Other (OTH)

AF:

0.622

AC:

1309

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1722

3443

5165

6886

8608

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

756

1512

2268

3024

3780

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.688

Hom.:

25850

Bravo

AF:

0.589

TwinsUK

AF:

0.746

AC:

2766

ALSPAC

AF:

0.716

AC:

2758

ESP6500AA

AF:

0.479

AC:

2112

ESP6500EA

AF:

0.728

AC:

6264

ExAC

AF:

0.623

AC:

75626

Asia WGS

AF:

0.415

AC:

1446

AN:

3478

EpiCase

AF:

0.728

EpiControl

AF:

0.722

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Apr 07, 2021

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.55

BayesDel_noAF

Benign

-0.43

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.028

.;T

Eigen

Benign

-0.24

Eigen_PC

Benign

-0.0096

FATHMM_MKL

Uncertain

0.83

LIST_S2

Benign

0.84

T;T

MetaRNN

Benign

0.0000016

T;T

MetaSVM

Benign

-0.98

MutationAssessor

Benign

1.0

.;L

PhyloP100

3.3

PrimateAI

Benign

0.47

PROVEAN

Benign

-1.9

.;N

REVEL

Benign

0.055

Sift

Benign

0.26

.;T

Sift4G

Benign

0.37

.;T

Polyphen

0.0040

.;B

Vest4

0.064

MPC

0.097

ClinPred

0.011

GERP RS

4.0

Varity_R

0.20

gMVP

0.53

Mutation Taster

=89/11

polymorphism (auto)

(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

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over