X-137030210-C-T

Variant names:

• chrX-137030210-C-T
• rs760719928
• NM_054021.2:c.1465G>A

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_054021.2(GPR101):​c.1465G>A​(p.Gly489Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000614 in 1,205,256 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 19 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 nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

• Frequency:
  • Genomes: 𝑓 0.000098 (0 hom., 1 hem., cov: 23)
  • Exomes 𝑓: 0.000058 (0 hom. 18 hem.)
• Consequence: GPR101 NM_054021.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.317
• Publications: 2 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: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.052613676).
• BS2: High Hemizygotes in GnomAdExome4 at 18 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.1465G>A	p.Gly489Arg	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.1465G>A	p.Gly489Arg	missense	Exon 2 of 2	ENSP00000498972.1	Q96P66
	ENSG00000291054	ENST00000693626.3		n.404-30315C>T		intron	N/A
	ENSG00000291054	ENST00000759385.1		n.500-30315C>T		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.0000981 AC: 11 AN: 112145 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.000195

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: 0.0000939

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000288 AC: 5 AN: 173759 AF XY: 0.0000507

Gnomad AFR exome AF: 0.000153

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: 0.0000256

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000576 AC: 63 AN: 1093111 Hom.: 0 Cov.: 31 AF XY: 0.0000501 AC XY: 18 AN XY: 359443

African (AFR) AF: 0.00 AC: 0 AN: 26305

American (AMR) AF: 0.00 AC: 0 AN: 34737

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18988

East Asian (EAS) AF: 0.00 AC: 0 AN: 30196

South Asian (SAS) AF: 0.0000949 AC: 5 AN: 52670

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40340

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4108

European-Non Finnish (NFE) AF: 0.0000655 AC: 55 AN: 839875

Other (OTH) AF: 0.0000654 AC: 3 AN: 45892

GnomAD4 genome AF: 0.0000981 AC: 11 AN: 112145 Hom.: 0 Cov.: 23 AF XY: 0.0000291 AC XY: 1 AN XY: 34313

African (AFR) AF: 0.000195 AC: 6 AN: 30817

American (AMR) AF: 0.00 AC: 0 AN: 10661

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2641

East Asian (EAS) AF: 0.00 AC: 0 AN: 3584

South Asian (SAS) AF: 0.00 AC: 0 AN: 2665

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6131

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

European-Non Finnish (NFE) AF: 0.0000939 AC: 5 AN: 53220

Other (OTH) AF: 0.00 AC: 0 AN: 1505

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000604

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

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	0.15
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.81
CADD	Benign	14
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0021	T
FATHMM_MKL	Benign	0.058	N
LIST_S2	Benign	0.46	T
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.053	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.81	L
PhyloP100		0.32
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.077
Sift	Uncertain	0.021	D
Sift4G	Benign	0.15	T
Polyphen		0.49	P
Vest4		0.078
MutPred		0.17		Loss of glycosylation at T490 (P = 0.0603)
MVP		0.43
MPC		1.5
ClinPred		0.068	T
GERP RS		3.4
Varity_R		0.062
Mutation Taster		=98/2	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: rs760719928; hg19: chrX-136112369; COSMIC: COSV99981483;