X-137030548-A-G

Variant names:

• chrX-137030548-A-G
• rs5931046
• NM_054021.2:c.1127T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_054021.2(GPR101):​c.1127T>C​(p.Leu376Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.158 in 1,207,840 control chromosomes in the GnomAD database, including 10,271 homozygotes. There are 64,138 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.17 (1231 hom., 5335 hem., cov: 22)
  • Exomes 𝑓: 0.16 (9040 hom. 58803 hem.)
• Consequence: GPR101 NM_054021.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.524
• Publications: 19 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0038969219).
• BP6: Variant X-137030548-A-G is Benign according to our data. Variant chrX-137030548-A-G is described in ClinVar as Benign. ClinVar VariationId is 1563029.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.275 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GPR101	NM_054021.2	MANE Select	c.1127T>C	p.Leu376Pro	missense	Exon 2 of 2	NP_473362.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GPR101	ENST00000651716.2	MANE Select	c.1127T>C	p.Leu376Pro	missense	Exon 2 of 2	ENSP00000498972.1
	ENSG00000291054	ENST00000693626.3		n.404-29977A>G		intron	N/A
	ENSG00000291054	ENST00000759385.1		n.500-29977A>G		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.172 AC: 18950 AN: 110220 Hom.: 1230 Cov.: 22

Gnomad AFR AF: 0.229

Gnomad AMI AF: 0.187

Gnomad AMR AF: 0.131

Gnomad ASJ AF: 0.186

Gnomad EAS AF: 0.114

Gnomad SAS AF: 0.297

Gnomad FIN AF: 0.129

Gnomad MID AF: 0.199

Gnomad NFE AF: 0.149

Gnomad OTH AF: 0.164

GnomAD2 exomes AF: 0.168 AC: 30519 AN: 181902 AF XY: 0.176

Gnomad AFR exome AF: 0.235

Gnomad AMR exome AF: 0.111

Gnomad ASJ exome AF: 0.192

Gnomad EAS exome AF: 0.125

Gnomad FIN exome AF: 0.138

Gnomad NFE exome AF: 0.152

Gnomad OTH exome AF: 0.182

GnomAD4 exome AF: 0.157 AC: 171861 AN: 1097567 Hom.: 9040 Cov.: 32 AF XY: 0.162 AC XY: 58803 AN XY: 362943

African (AFR) AF: 0.238 AC: 6289 AN: 26395

American (AMR) AF: 0.115 AC: 4047 AN: 35174

Ashkenazi Jewish (ASJ) AF: 0.193 AC: 3725 AN: 19339

East Asian (EAS) AF: 0.106 AC: 3207 AN: 30204

South Asian (SAS) AF: 0.302 AC: 16302 AN: 53947

European-Finnish (FIN) AF: 0.138 AC: 5576 AN: 40507

Middle Eastern (MID) AF: 0.200 AC: 827 AN: 4133

European-Non Finnish (NFE) AF: 0.147 AC: 124077 AN: 841799

Other (OTH) AF: 0.170 AC: 7811 AN: 46069

GnomAD4 genome AF: 0.172 AC: 18950 AN: 110273 Hom.: 1231 Cov.: 22 AF XY: 0.164 AC XY: 5335 AN XY: 32611

African (AFR) AF: 0.229 AC: 6912 AN: 30214

American (AMR) AF: 0.131 AC: 1372 AN: 10470

Ashkenazi Jewish (ASJ) AF: 0.186 AC: 488 AN: 2629

East Asian (EAS) AF: 0.114 AC: 398 AN: 3495

South Asian (SAS) AF: 0.292 AC: 733 AN: 2506

European-Finnish (FIN) AF: 0.129 AC: 760 AN: 5909

Middle Eastern (MID) AF: 0.205 AC: 44 AN: 215

European-Non Finnish (NFE) AF: 0.149 AC: 7861 AN: 52656

Other (OTH) AF: 0.170 AC: 255 AN: 1501

Alfa AF: 0.162 Hom.: 14070

Bravo AF: 0.174

TwinsUK AF: 0.159 AC: 589

ALSPAC AF: 0.150 AC: 432

ESP6500AA AF: 0.214 AC: 820

ESP6500EA AF: 0.148 AC: 993

ExAC AF: 0.175 AC: 21192

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.59	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0058	T
FATHMM_MKL	Benign	0.063	N
LIST_S2	Benign	0.42	T
MetaRNN	Benign	0.0039	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.5	L
PhyloP100		0.52
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-0.94	N
REVEL	Benign	0.095
Sift	Benign	0.12	T
Sift4G	Uncertain	0.054	T
Polyphen		0.77	P
Vest4		0.10
MPC		1.6
ClinPred		0.027	T
GERP RS		2.8
Varity_R		0.17
Mutation Taster		=96/4	polymorphism (auto)

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

Other links and lift over

dbSNP: rs5931046; hg19: chrX-136112707; COSMIC: COSV53239500;