X-137030534-G-A

Variant names:

• chrX-137030534-G-A
• rs137929096
• NM_054021.2:c.1141C>T

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_054021.2(GPR101):​c.1141C>T​(p.Arg381Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000554 in 1,208,500 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 14 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R381H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00013 (0 hom., 4 hem., cov: 23)
  • Exomes 𝑓: 0.000048 (0 hom. 10 hem.)
• Consequence: GPR101 NM_054021.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.51
• Publications: 0 publications found

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

ENSG00000291054 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.17195502).
• BS2: High Hemizygotes in GnomAd4 at 4 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.1141C>T	p.Arg381Cys	missense	Exon 2 of 2	NP_473362.1	Q96P66

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GPR101	ENST00000651716.2	MANE Select	c.1141C>T	p.Arg381Cys	missense	Exon 2 of 2	ENSP00000498972.1	Q96P66
	ENSG00000291054	ENST00000693626.3		n.404-29991G>A		intron	N/A
	ENSG00000291054	ENST00000759385.1		n.500-29991G>A		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.000126 AC: 14 AN: 111154 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.000164

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000170

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000331 AC: 6 AN: 181507 AF XY: 0.0000151

Gnomad AFR exome AF: 0.000228

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000370

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000483 AC: 53 AN: 1097346 Hom.: 0 Cov.: 31 AF XY: 0.0000276 AC XY: 10 AN XY: 362744

African (AFR) AF: 0.000189 AC: 5 AN: 26398

American (AMR) AF: 0.00 AC: 0 AN: 35173

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19303

East Asian (EAS) AF: 0.00 AC: 0 AN: 30204

South Asian (SAS) AF: 0.00 AC: 0 AN: 53881

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40496

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4132

European-Non Finnish (NFE) AF: 0.0000547 AC: 46 AN: 841697

Other (OTH) AF: 0.0000434 AC: 2 AN: 46062

GnomAD4 genome AF: 0.000126 AC: 14 AN: 111154 Hom.: 0 Cov.: 23 AF XY: 0.000120 AC XY: 4 AN XY: 33344

African (AFR) AF: 0.000164 AC: 5 AN: 30498

American (AMR) AF: 0.00 AC: 0 AN: 10535

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2644

East Asian (EAS) AF: 0.00 AC: 0 AN: 3554

South Asian (SAS) AF: 0.00 AC: 0 AN: 2563

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5988

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 238

European-Non Finnish (NFE) AF: 0.000170 AC: 9 AN: 52951

Other (OTH) AF: 0.00 AC: 0 AN: 1495

Alfa AF: 0.0000764 Hom.: 3

Bravo AF: 0.000140

ESP6500AA AF: 0.000522 AC: 2

ESP6500EA AF: 0.000297 AC: 2

ExAC AF: 0.0000412 AC: 5

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.0074	T
FATHMM_MKL	Benign	0.15	N
LIST_S2	Benign	0.70	T
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.17	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.9	L
PhyloP100		2.5
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.14
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.010	D
Polyphen		0.99	D
Vest4		0.19
MVP		0.80
MPC		1.5
ClinPred		0.22	T
GERP RS		3.5
Varity_R		0.22
Mutation Taster		=99/1	polymorphism

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

Other links and lift over

dbSNP: rs137929096; hg19: chrX-136112693; COSMIC: COSV108839052;