rs73637412

chrX-137030751-C-GchrX-137030751-C-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

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. 13/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. E308E) has been classified as Likely benign.

• 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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1 B:4 O:1
• Conservation: PhyloP100: -1.90

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -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 id is 167871.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, not_provided=1, Uncertain_significance=1}. Variant chrX-137030751-C-G is described in Lovd as [Likely_benign].
• BS2: High Hemizygotes in GnomAd at 91 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GPR101	NM_054021.2	c.924G>C	p.Glu308Asp	missense_variant	2/2	ENST00000651716.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GPR101	ENST00000651716.2	c.924G>C	p.Glu308Asp	missense_variant	2/2		NM_054021.2	P1
	ENST00000693626.2	n.394-29774C>G		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.00344 AC: 382 AN: 110993 Hom.: 1 Cov.: 22 AF XY: 0.00274 AC XY: 91 AN XY: 33195

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

GnomAD3 exomes AF: 0.00353 AC: 647 AN: 183283 Hom.: 1 AF XY: 0.00365 AC XY: 247 AN XY: 67727

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 SAS exome AF: 0.00131

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.: 14 Cov.: 32 AF XY: 0.00499 AC XY: 1812 AN XY: 363479

Gnomad4 AFR exome AF: 0.000720

Gnomad4 AMR exome AF: 0.000625

Gnomad4 ASJ exome AF: 0.00882

Gnomad4 EAS exome AF: 0.0000662

Gnomad4 SAS exome AF: 0.00151

Gnomad4 FIN exome AF: 0.00418

Gnomad4 NFE exome AF: 0.00557

Gnomad4 OTH exome AF: 0.00449

GnomAD4 genome AF: 0.00344 AC: 382 AN: 111047 Hom.: 1 Cov.: 22 AF XY: 0.00274 AC XY: 91 AN XY: 33259

Gnomad4 AFR AF: 0.000688

Gnomad4 AMR AF: 0.00104

Gnomad4 ASJ AF: 0.00949

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00117

Gnomad4 FIN AF: 0.00303

Gnomad4 NFE AF: 0.00571

Gnomad4 OTH AF: 0.00133

Alfa AF: 0.00285 Hom.: 23

Bravo AF: 0.00323

TwinsUK AF: 0.00593 AC: 22

ALSPAC AF: 0.00450 AC: 13

ExAC AF: 0.00360 AC: 437

EpiCase AF: 0.00545

EpiControl AF: 0.00486

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1 Benign:4 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Pituitary adenoma, growth hormone-secreting, 2 Pathogenic:1 Uncertain:1 Other:1

Pathogenic, no assertion criteria provided	literature only	OMIM	Mar 26, 2015	- -
not provided, no classification provided	literature only	GeneReviews	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

not provided Benign:3

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Dec 22, 2023	- -

GPR101-related condition Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 03, 2020

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.083
BayesDel_addAF	Benign	-0.71	T
BayesDel_noAF	Benign	-0.79
Cadd	Benign	0.19
Dann	Benign	0.41
DEOGEN2	Benign	0.0026	T
FATHMM_MKL	Benign	0.032	N
LIST_S2	Benign	0.38	T
M_CAP	Uncertain	0.18	D
MetaRNN	Benign	0.0047	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.69	N
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-0.53	N
REVEL	Benign	0.028
Sift	Benign	0.13	T
Sift4G	Benign	0.068	T
Polyphen		0.0010	B
Vest4		0.033
MutPred		0.18		Gain of glycosylation at S309 (P = 0.1215);
MVP		0.51
MPC		0.43
ClinPred		0.0029	T
GERP RS		-5.2
Varity_R		0.057

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

LitVar

Other links and lift over

dbSNP: rs73637412; hg19: chrX-136112910; COSMIC: COSV53238460;