X-102714932-G-C

Variant names:

• chrX-102714932-G-C
• rs137939858
• NM_001004051.4:c.63G>C

Variant summary

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

The NM_001004051.4(GPRASP2):​c.63G>C​(p.Glu21Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00236 in 1,211,335 control chromosomes in the GnomAD database, including 5 homozygotes. There are 889 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0014 (0 hom., 45 hem., cov: 24)
  • Exomes 𝑓: 0.0025 (5 hom. 844 hem.)
• Consequence: GPRASP2 NM_001004051.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1 B:1
• Conservation: PhyloP100: 0.752
• Publications: 1 publications found

Genes affected

GPRASP2 (HGNC:25169): (G protein-coupled receptor associated sorting protein 2) The protein encoded by this gene is a member of a family that regulates the activity of G protein-coupled receptors (GPCRs). The encoded protein has been shown to be capable of interacting with several GPCRs, including the M1 muscarinic acetylcholine receptor and the calcitonin receptor. Several transcript variants encoding the same protein have been found for this gene. [provided by RefSeq, May 2010]

ARMCX5-GPRASP2 (HGNC:42000): (ARMCX5-GPRASP2 readthrough) This locus represents naturally occurring readthrough transcription among the adjacent armadillo repeat containing, X-linked 5 (ARMCX5), G protein-coupled receptor associated sorting proteins 1 and 2 (GPRASP1 and GPRASP2), basic helix-loop-helix family member b9 (BHLHB9), and long intergenic non-protein coding RNA 630 (LINC00630) genes on chromosome X. Transcripts may make use of multiple alternative promoters and polyadenylation signals in this region. Readthrough transcripts may produce proteins identical to the proteins encoded by GPRASP2 or BHLHB9. [provided by RefSeq, Apr 2017]

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0074768364).
• BS2: High Hemizygotes in GnomAd4 at 45 Unknown,XL gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001004051.4. 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
	GPRASP2	NM_001004051.4	MANE Select	c.63G>C	p.Glu21Asp	missense	Exon 5 of 5	NP_001004051.1	Q96D09
	GPRASP2	NM_001184874.3		c.63G>C	p.Glu21Asp	missense	Exon 5 of 5	NP_001171803.1	Q96D09
	GPRASP2	NM_001184875.3		c.63G>C	p.Glu21Asp	missense	Exon 4 of 4	NP_001171804.1	Q96D09

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GPRASP2	ENST00000483720.7	TSL:2 MANE Select	c.63G>C	p.Glu21Asp	missense	Exon 5 of 5	ENSP00000507692.1	Q96D09
	GPRASP2	ENST00000332262.10	TSL:1	c.63G>C	p.Glu21Asp	missense	Exon 4 of 4	ENSP00000339057.3	Q96D09
	ARMCX5-GPRASP2	ENST00000652409.1		c.-756+666G>C		intron	N/A	ENSP00000498643.1

Frequencies

GnomAD3 genomes AF: 0.00143 AC: 162 AN: 113100 Hom.: 0 Cov.: 24

Gnomad AFR AF: 0.000321

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00102

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000635

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00253

Gnomad OTH AF: 0.00132

GnomAD2 exomes AF: 0.00124 AC: 227 AN: 183363 AF XY: 0.00125

Gnomad AFR exome AF: 0.000304

Gnomad AMR exome AF: 0.000802

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000500

Gnomad NFE exome AF: 0.00227

Gnomad OTH exome AF: 0.00155

GnomAD4 exome AF: 0.00246 AC: 2697 AN: 1098235 Hom.: 5 Cov.: 31 AF XY: 0.00232 AC XY: 844 AN XY: 363589

African (AFR) AF: 0.000152 AC: 4 AN: 26401

American (AMR) AF: 0.000739 AC: 26 AN: 35205

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19383

East Asian (EAS) AF: 0.0000662 AC: 2 AN: 30205

South Asian (SAS) AF: 0.00 AC: 0 AN: 54139

European-Finnish (FIN) AF: 0.000543 AC: 22 AN: 40532

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4136

European-Non Finnish (NFE) AF: 0.00305 AC: 2572 AN: 842136

Other (OTH) AF: 0.00154 AC: 71 AN: 46098

GnomAD4 genome AF: 0.00143 AC: 162 AN: 113100 Hom.: 0 Cov.: 24 AF XY: 0.00128 AC XY: 45 AN XY: 35234

African (AFR) AF: 0.000321 AC: 10 AN: 31171

American (AMR) AF: 0.00102 AC: 11 AN: 10777

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2654

East Asian (EAS) AF: 0.00 AC: 0 AN: 3601

South Asian (SAS) AF: 0.00 AC: 0 AN: 2776

European-Finnish (FIN) AF: 0.000635 AC: 4 AN: 6296

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 239

European-Non Finnish (NFE) AF: 0.00253 AC: 135 AN: 53384

Other (OTH) AF: 0.00132 AC: 2 AN: 1515

Alfa AF: 0.00220 Hom.: 43

Bravo AF: 0.00143

TwinsUK AF: 0.00297 AC: 11

ALSPAC AF: 0.00485 AC: 14

ESP6500AA AF: 0.000522 AC: 2

ESP6500EA AF: 0.00357 AC: 24

ExAC AF: 0.00142 AC: 172

EpiCase AF: 0.00245

EpiControl AF: 0.00314

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	GPRASP2-related disorder (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.76	T
BayesDel_noAF	Benign	-0.86
CADD	Benign	17
DANN	Uncertain	0.99
DEOGEN2	Benign	0.016	T
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Benign	0.72	T
M_CAP	Benign	0.0057	T
MetaRNN	Benign	0.0075	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		0.75
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-0.78	N
REVEL	Benign	0.027
Sift	Benign	0.071	T
Sift4G	Uncertain	0.025	D
Polyphen		0.82	P
Vest4		0.047
MutPred		0.12		Gain of ubiquitination at K16 (P = 0.1079)
MVP		0.30
MPC		0.35
ClinPred		0.013	T
GERP RS		2.6
Varity_R		0.12
gMVP		0.077
Mutation Taster		=100/0	polymorphism (auto)

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: rs137939858; hg19: chrX-101969860;