X-102715567-C-T

Position:

• chrX-102715567-C-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_001004051.4(GPRASP2):​c.698C>T​(p.Ala233Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000595 in 1,209,896 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 224 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 Benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.00040 (0 hom., 14 hem., cov: 23)
  • Exomes 𝑓: 0.00061 (0 hom. 210 hem.)
• Consequence: GPRASP2 NM_001004051.4 missense
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: 1.60

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

Verdict is Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009398907).
• BP6: Variant X-102715567-C-T is Benign according to our data. Variant chrX-102715567-C-T is described in ClinVar as [Benign]. Clinvar id is 3050159.Status of the report is no_assertion_criteria_provided, 0 stars.
• BS2: High Hemizygotes in GnomAd4 at 14 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GPRASP2	NM_001004051.4	c.698C>T	p.Ala233Val	missense_variant	5/5	ENST00000483720.7
ARMCX5-GPRASP2	NR_146584.3	n.795+1301C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GPRASP2	ENST00000483720.7	c.698C>T	p.Ala233Val	missense_variant	5/5	2	NM_001004051.4	P1
ARMCX5-GPRASP2	ENST00000652409.1	c.-756+1301C>T		intron_variant				P1

Frequencies

GnomAD3 genomes AF: 0.000403 AC: 45 AN: 111637 Hom.: 0 Cov.: 23 AF XY: 0.000414 AC XY: 14 AN XY: 33829

Gnomad AFR AF: 0.0000978

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000663

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00149

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000452

Gnomad OTH AF: 0.00133

GnomAD3 exomes AF: 0.000398 AC: 73 AN: 183267 Hom.: 0 AF XY: 0.000384 AC XY: 26 AN XY: 67779

Gnomad AFR exome AF: 0.0000762

Gnomad AMR exome AF: 0.000365

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000721

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00125

Gnomad NFE exome AF: 0.000465

Gnomad OTH exome AF: 0.000663

GnomAD4 exome AF: 0.000615 AC: 675 AN: 1098259 Hom.: 0 Cov.: 31 AF XY: 0.000578 AC XY: 210 AN XY: 363615

Gnomad4 AFR exome AF: 0.0000757

Gnomad4 AMR exome AF: 0.000568

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000331

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000888

Gnomad4 NFE exome AF: 0.000691

Gnomad4 OTH exome AF: 0.000738

GnomAD4 genome AF: 0.000403 AC: 45 AN: 111637 Hom.: 0 Cov.: 23 AF XY: 0.000414 AC XY: 14 AN XY: 33829

Gnomad4 AFR AF: 0.0000978

Gnomad4 AMR AF: 0.000663

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00149

Gnomad4 NFE AF: 0.000452

Gnomad4 OTH AF: 0.00133

Alfa AF: 0.000504 Hom.: 21

Bravo AF: 0.000434

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00138 AC: 4

ESP6500AA AF: 0.000261 AC: 1

ESP6500EA AF: 0.000446 AC: 3

ExAC AF: 0.000272 AC: 33

EpiCase AF: 0.000600

EpiControl AF: 0.000771

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

GPRASP2-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 10, 2022

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.057
BayesDel_addAF	Benign	-0.85	T
BayesDel_noAF	Benign	-1.1
CADD	Benign	1.3
DANN	Benign	0.74
DEOGEN2	Benign	0.0070	T;T;T
FATHMM_MKL	Benign	0.0060	N
LIST_S2	Benign	0.47	.;T;.
M_CAP	Benign	0.0033	T
MetaRNN	Benign	0.0094	T;T;T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	-1.3	N;N;N
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-0.62	N;N;N
REVEL	Benign	0.031
Sift	Benign	0.34	T;T;T
Sift4G	Benign	0.88	T;T;T
Polyphen		0.0	B;B;B
Vest4		0.034
MVP		0.32
MPC		0.14
ClinPred		0.0056	T
GERP RS		1.4
Varity_R		0.042
gMVP		0.047

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

Other links and lift over

dbSNP: rs200562810; hg19: chrX-101970495;