chrX-102715388-A-C

Variant names:

• chrX-102715388-A-C
• rs6616421
• NM_001004051.4:c.519A>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001004051.4(GPRASP2):​c.519A>C​(p.Arg173Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0129 in 1,211,143 control chromosomes in the GnomAD database, including 93 homozygotes. There are 5,689 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.013 (3 hom., 449 hem., cov: 24)
  • Exomes 𝑓: 0.013 (90 hom. 5240 hem.)
• Consequence: GPRASP2 NM_001004051.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.0610
• Publications: 5 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0021811128).
• BP6: Variant X-102715388-A-C is Benign according to our data. Variant chrX-102715388-A-C is described in ClinVar as Benign. ClinVar VariationId is 1183084.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.0132 (1487/112887) while in subpopulation EAS AF = 0.0507 (180/3548). AF 95% confidence interval is 0.0447. There are 3 homozygotes in GnomAd4. There are 449 alleles in the male GnomAd4 subpopulation. Median coverage is 24. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 3 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.519A>C	p.Arg173Ser	missense	Exon 5 of 5	NP_001004051.1	Q96D09
	GPRASP2	NM_001184874.3		c.519A>C	p.Arg173Ser	missense	Exon 5 of 5	NP_001171803.1	Q96D09
	GPRASP2	NM_001184875.3		c.519A>C	p.Arg173Ser	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.519A>C	p.Arg173Ser	missense	Exon 5 of 5	ENSP00000507692.1	Q96D09
	GPRASP2	ENST00000332262.10	TSL:1	c.519A>C	p.Arg173Ser	missense	Exon 4 of 4	ENSP00000339057.3	Q96D09
	ARMCX5-GPRASP2	ENST00000652409.1		c.-756+1122A>C		intron	N/A	ENSP00000498643.1

Frequencies

GnomAD3 genomes AF: 0.0132 AC: 1484 AN: 112835 Hom.: 3 Cov.: 24

Gnomad AFR AF: 0.0121

Gnomad AMI AF: 0.00146

Gnomad AMR AF: 0.00697

Gnomad ASJ AF: 0.0372

Gnomad EAS AF: 0.0500

Gnomad SAS AF: 0.0468

Gnomad FIN AF: 0.00448

Gnomad MID AF: 0.0126

Gnomad NFE AF: 0.0107

Gnomad OTH AF: 0.0145

GnomAD2 exomes AF: 0.0177 AC: 3245 AN: 183432 AF XY: 0.0200

Gnomad AFR exome AF: 0.0126

Gnomad AMR exome AF: 0.00441

Gnomad ASJ exome AF: 0.0290

Gnomad EAS exome AF: 0.0509

Gnomad FIN exome AF: 0.00556

Gnomad NFE exome AF: 0.0119

Gnomad OTH exome AF: 0.0126

GnomAD4 exome AF: 0.0129 AC: 14172 AN: 1098256 Hom.: 90 Cov.: 31 AF XY: 0.0144 AC XY: 5240 AN XY: 363614

African (AFR) AF: 0.0117 AC: 310 AN: 26403

American (AMR) AF: 0.00463 AC: 163 AN: 35207

Ashkenazi Jewish (ASJ) AF: 0.0301 AC: 583 AN: 19384

East Asian (EAS) AF: 0.0438 AC: 1324 AN: 30203

South Asian (SAS) AF: 0.0472 AC: 2557 AN: 54145

European-Finnish (FIN) AF: 0.00560 AC: 227 AN: 40533

Middle Eastern (MID) AF: 0.0324 AC: 134 AN: 4136

European-Non Finnish (NFE) AF: 0.00950 AC: 8000 AN: 842147

Other (OTH) AF: 0.0190 AC: 874 AN: 46098

GnomAD4 genome AF: 0.0132 AC: 1487 AN: 112887 Hom.: 3 Cov.: 24 AF XY: 0.0128 AC XY: 449 AN XY: 35041

African (AFR) AF: 0.0121 AC: 376 AN: 31136

American (AMR) AF: 0.00696 AC: 75 AN: 10777

Ashkenazi Jewish (ASJ) AF: 0.0372 AC: 99 AN: 2663

East Asian (EAS) AF: 0.0507 AC: 180 AN: 3548

South Asian (SAS) AF: 0.0469 AC: 128 AN: 2727

European-Finnish (FIN) AF: 0.00448 AC: 28 AN: 6249

Middle Eastern (MID) AF: 0.0138 AC: 3 AN: 218

European-Non Finnish (NFE) AF: 0.0107 AC: 573 AN: 53343

Other (OTH) AF: 0.0156 AC: 24 AN: 1540

Alfa AF: 0.0142 Hom.: 644

Bravo AF: 0.0130

TwinsUK AF: 0.00917 AC: 34

ALSPAC AF: 0.00865 AC: 25

ESP6500AA AF: 0.0143 AC: 55

ESP6500EA AF: 0.0122 AC: 82

ExAC AF: 0.0199 AC: 2412

EpiCase AF: 0.0158

EpiControl AF: 0.0143

ClinVar

ClinVar submissions

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	0.21
BayesDel_addAF	Benign	-0.76	T
BayesDel_noAF	Benign	-0.82
CADD	Benign	7.8
DANN	Benign	0.88
DEOGEN2	Benign	0.020	T
FATHMM_MKL	Benign	0.077	N
LIST_S2	Benign	0.73	T
MetaRNN	Benign	0.0022	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.8	M
PhyloP100		0.061
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.0030
Sift	Benign	0.14	T
Sift4G	Benign	0.14	T
Polyphen		0.010	B
Vest4		0.043
MutPred		0.33		Gain of disorder (P = 0.0354)
MPC		0.16
ClinPred		0.0076	T
GERP RS		-0.90
Varity_R		0.18
gMVP		0.26
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: rs6616421; hg19: chrX-101970316; COSMIC: COSV59991419; COSMIC: COSV59991419;