X-137030751-C-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_054021.2(GPR101):c.924G>C(p.Glu308Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00476 in 1,209,166 control chromosomes in the GnomAD database, including 15 homozygotes. There are 1,903 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E308K) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0034 ( 1 hom., 91 hem., cov: 22)

Exomes 𝑓: 0.0049 ( 14 hom. 1812 hem. )

Consequence

GPR101
NM_054021.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:1B:4O:1

Conservation

PhyloP100: -1.90

Publications

28 publications found

Variant links:

Genes affected

GPR101 (HGNC:14963): (G protein-coupled receptor 101) The protein encoded by this gene is an orphan G protein-coupled receptor of unknown function. The encoded protein is a member of a family of proteins that contain seven transmembrane domains and transduce extracellular signals through heterotrimeric G proteins. [provided by RefSeq, Sep 2011]

GPR101 Gene-Disease associations (from GenCC):

pituitary adenoma, growth hormone-secreting, 2
Inheritance: XL Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
acromegaly
Inheritance: Unknown Classification: SUPPORTIVE Submitted by: Orphanet

GPR101 links:

ENSG00000291054 (HGNC:):

ENSG00000291054 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.004725307).

BP6

Variant X-137030751-C-G is Benign according to our data. Variant chrX-137030751-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 167871.

BS2

High Hemizygotes in GnomAd4 at 91 XL,Unknown gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_054021.2. 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
	GPR101	NM_054021.2	MANE Select	c.924G>C	p.Glu308Asp	missense	Exon 2 of 2	NP_473362.1	Q96P66

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
GPR101	ENST00000651716.2	MANE Select	c.924G>C	p.Glu308Asp	missense	Exon 2 of 2	ENSP00000498972.1	Q96P66
ENSG00000291054	ENST00000693626.3		n.404-29774C>G		intron	N/A
ENSG00000291054	ENST00000759385.1		n.500-29774C>G		intron	N/A

Frequencies

GnomAD3 genomes

AF:

0.00344

AC:

382

AN:

110993

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000690

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00104

Gnomad ASJ

AF:

0.00949

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00117

Gnomad FIN

AF:

0.00303

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00571

Gnomad OTH

AF:

0.00135

GnomAD2 exomes

AF:

0.00353

AC:

647

AN:

183283

AF XY:

0.00365

show subpopulations

Gnomad AFR exome

AF:

0.000380

Gnomad AMR exome

AF:

0.000729

Gnomad ASJ exome

AF:

0.00815

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00453

Gnomad NFE exome

AF:

0.00540

Gnomad OTH exome

AF:

0.00485

GnomAD4 exome

AF:

0.00489

AC:

5368

AN:

1098119

Hom.:

Cov.:

AF XY:

0.00499

AC XY:

1812

AN XY:

363479

show subpopulations

African (AFR)

AF:

0.000720

AC:

AN:

26403

American (AMR)

AF:

0.000625

AC:

AN:

35207

Ashkenazi Jewish (ASJ)

AF:

0.00882

AC:

171

AN:

19386

East Asian (EAS)

AF:

0.0000662

AC:

AN:

30206

South Asian (SAS)

AF:

0.00151

AC:

AN:

54143

European-Finnish (FIN)

AF:

0.00418

AC:

169

AN:

40453

Middle Eastern (MID)

AF:

0.00193

AC:

AN:

4137

European-Non Finnish (NFE)

AF:

0.00557

AC:

4688

AN:

842089

Other (OTH)

AF:

0.00449

AC:

207

AN:

46095

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.487

Heterozygous variant carriers

238

475

713

950

1188

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

172

344

516

688

860

<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:

0.00344

AC:

382

AN:

111047

Hom.:

Cov.:

AF XY:

0.00274

AC XY:

AN XY:

33259

show subpopulations

African (AFR)

AF:

0.000688

AC:

AN:

30503

American (AMR)

AF:

0.00104

AC:

AN:

10553

Ashkenazi Jewish (ASJ)

AF:

0.00949

AC:

AN:

2633

East Asian (EAS)

AF:

0.00

AC:

AN:

3511

South Asian (SAS)

AF:

0.00117

AC:

AN:

2562

European-Finnish (FIN)

AF:

0.00303

AC:

AN:

5950

Middle Eastern (MID)

AF:

0.00

AC:

AN:

217

European-Non Finnish (NFE)

AF:

0.00571

AC:

302

AN:

52926

Other (OTH)

AF:

0.00133

AC:

AN:

1504

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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

Alfa

AF:

0.00285

Hom.:

Bravo

AF:

0.00323

TwinsUK

AF:

0.00593

AC:

ALSPAC

AF:

0.00450

AC:

ExAC

AF:

0.00360

AC:

437

EpiCase

AF:

0.00545

EpiControl

AF:

0.00486

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

Pituitary adenoma, growth hormone-secreting, 2 (3)

GPR101-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.083

BayesDel_addAF

Benign

-0.71

BayesDel_noAF

Benign

-0.79

CADD

Benign

0.19

(source)

DANN

Benign

0.41

DEOGEN2

Benign

0.0026

FATHMM_MKL

Benign

0.032

LIST_S2

Benign

0.38

M_CAP

Uncertain

0.18

MetaRNN

Benign

0.0047

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.69

PhyloP100

-1.9

PrimateAI

Benign

0.25

PROVEAN

Benign

-0.53

REVEL

Benign

0.028

Sift

Benign

0.13

Sift4G

Benign

0.068

Polyphen

0.0010

Vest4

0.033

MutPred

0.18

Gain of glycosylation at S309 (P = 0.1215)

MVP

0.51

MPC

0.43

ClinPred

0.0029

GERP RS

-5.2

Varity_R

0.057

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over