NM_001004051.4:c.519A>C

Variant names:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

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. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

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

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.0610

Variant links:

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]

GPRASP2 links:

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]

ARMCX5-GPRASP2 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 id 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 male gnomad4 subpopulation. Median coverage is 24. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 3 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GPRASP2	NM_001004051.4 link	c.519A>C	p.Arg173Ser	missense_variant	Exon 5 of 5	ENST00000483720.7	NP_001004051.1	Q96D09B3KW05

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GPRASP2	ENST00000483720.7 link	c.519A>C	p.Arg173Ser	missense_variant	Exon 5 of 5	2	NM_001004051.4	ENSP00000507692.1		Q96D09
ARMCX5-GPRASP2	ENST00000652409.1 link	c.-756+1122A>C		intron_variant	Intron 4 of 7			ENSP00000498643.1

Frequencies

GnomAD3 genomes

AF:

0.0132

AC:

1484

AN:

112835

Hom.:

Cov.:

AF XY:

0.0128

AC XY:

447

AN XY:

34979

show subpopulations

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

GnomAD3 exomes

AF:

0.0177

AC:

3245

AN:

183432

Hom.:

AF XY:

0.0200

AC XY:

1357

AN XY:

67890

show subpopulations

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 SAS exome

AF:

0.0480

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.:

Cov.:

AF XY:

0.0144

AC XY:

5240

AN XY:

363614

show subpopulations

Gnomad4 AFR exome

AF:

0.0117

Gnomad4 AMR exome

AF:

0.00463

Gnomad4 ASJ exome

AF:

0.0301

Gnomad4 EAS exome

AF:

0.0438

Gnomad4 SAS exome

AF:

0.0472

Gnomad4 FIN exome

AF:

0.00560

Gnomad4 NFE exome

AF:

0.00950

Gnomad4 OTH exome

AF:

0.0190

GnomAD4 genome

AF:

0.0132

AC:

1487

AN:

112887

Hom.:

Cov.:

AF XY:

0.0128

AC XY:

449

AN XY:

35041

show subpopulations

Gnomad4 AFR

AF:

0.0121

Gnomad4 AMR

AF:

0.00696

Gnomad4 ASJ

AF:

0.0372

Gnomad4 EAS

AF:

0.0507

Gnomad4 SAS

AF:

0.0469

Gnomad4 FIN

AF:

0.00448

Gnomad4 NFE

AF:

0.0107

Gnomad4 OTH

AF:

0.0156

Alfa

AF:

0.0142

Hom.:

598

Bravo

AF:

0.0130

TwinsUK

AF:

0.00917

AC:

ALSPAC

AF:

0.00865

AC:

ESP6500AA

AF:

0.0143

AC:

ESP6500EA

AF:

0.0122

AC:

ExAC

AF:

0.0199

AC:

2412

EpiCase

AF:

0.0158

EpiControl

AF:

0.0143

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

May 05, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.21

BayesDel_addAF

Benign

-0.76

BayesDel_noAF

Benign

-0.82

CADD

Benign

7.8

DANN

Benign

0.88

DEOGEN2

Benign

0.020

T;T;T

FATHMM_MKL

Benign

0.077

LIST_S2

Benign

0.73

.;T;.

MetaRNN

Benign

0.0022

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.8

M;M;M

PrimateAI

Benign

0.33

PROVEAN

Benign

-1.4

N;N;N

REVEL

Benign

0.0030

Sift

Benign

0.14

T;T;T

Sift4G

Benign

0.14

T;T;T

Polyphen

0.010

B;B;B

Vest4

0.043

MutPred

0.33

Gain of disorder (P = 0.0354);Gain of disorder (P = 0.0354);Gain of disorder (P = 0.0354);

MPC

0.16

ClinPred

0.0076

GERP RS

-0.90

Varity_R

0.18

gMVP

0.26

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over