X-137030573-C-T

Variant names:

• chrX-137030573-C-T
• rs149334737
• NM_054021.2:c.1102G>A

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_Moderate BP6 BS2

The NM_054021.2(GPR101):​c.1102G>A​(p.Glu368Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000356 in 1,209,184 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 134 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E368V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00016 (0 hom., 3 hem., cov: 23)
  • Exomes 𝑓: 0.00038 (0 hom. 131 hem.)
• Consequence: GPR101 NM_054021.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 1.64
• 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 -7 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.13601142).
• BP6: Variant X-137030573-C-T is Benign according to our data. Variant chrX-137030573-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 2193756.
• BS2: High Hemizygotes in GnomAd4 at 3 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.1102G>A	p.Glu368Lys	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.1102G>A	p.Glu368Lys	missense	Exon 2 of 2	ENSP00000498972.1	Q96P66
	ENSG00000291054	ENST00000693626.3		n.404-29952C>T		intron	N/A
	ENSG00000291054	ENST00000759385.1		n.500-29952C>T		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.000162 AC: 18 AN: 111236 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000948

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: 0.000321

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000240 AC: 44 AN: 183038 AF XY: 0.000207

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000730

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000250

Gnomad NFE exome AF: 0.000440

Gnomad OTH exome AF: 0.000442

GnomAD4 exome AF: 0.000376 AC: 413 AN: 1097948 Hom.: 0 Cov.: 32 AF XY: 0.000361 AC XY: 131 AN XY: 363318

African (AFR) AF: 0.0000379 AC: 1 AN: 26400

American (AMR) AF: 0.000114 AC: 4 AN: 35194

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19362

East Asian (EAS) AF: 0.00 AC: 0 AN: 30206

South Asian (SAS) AF: 0.00 AC: 0 AN: 54077

European-Finnish (FIN) AF: 0.000148 AC: 6 AN: 40520

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4134

European-Non Finnish (NFE) AF: 0.000456 AC: 384 AN: 841965

Other (OTH) AF: 0.000391 AC: 18 AN: 46090

GnomAD4 genome AF: 0.000162 AC: 18 AN: 111236 Hom.: 0 Cov.: 23 AF XY: 0.0000898 AC XY: 3 AN XY: 33406

African (AFR) AF: 0.00 AC: 0 AN: 30521

American (AMR) AF: 0.0000948 AC: 1 AN: 10554

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2648

East Asian (EAS) AF: 0.00 AC: 0 AN: 3553

South Asian (SAS) AF: 0.00 AC: 0 AN: 2557

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6001

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 237

European-Non Finnish (NFE) AF: 0.000321 AC: 17 AN: 52977

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

Alfa AF: 0.000314 Hom.: 16

Bravo AF: 0.000128

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.000346 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000446 AC: 3

ExAC AF: 0.000222 AC: 27

EpiCase AF: 0.000327

EpiControl AF: 0.000237

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.096
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	19
DANN	Uncertain	1.0
DEOGEN2	Benign	0.0015	T
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Benign	0.67	T
M_CAP	Benign	0.041	D
MetaRNN	Benign	0.14	T
MetaSVM	Benign	-0.84	T
MutationAssessor	Benign	1.9	L
PhyloP100		1.6
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-0.45	N
REVEL	Benign	0.17
Sift	Benign	0.14	T
Sift4G	Benign	0.066	T
Polyphen		0.98	D
Vest4		0.14
MVP		0.77
MPC		0.58
ClinPred		0.054	T
GERP RS		3.4
Varity_R		0.13
Mutation Taster		=96/4	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: rs149334737; hg19: chrX-136112732;