X-102749947-T-C

Position:

• chrX-102749947-T-C

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_001142524.2(GPRASP3):​c.952T>C​(p.Cys318Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00669 in 1,207,457 control chromosomes in the GnomAD database, including 13 homozygotes. There are 2,590 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.0049 (1 hom., 163 hem., cov: 23)
  • Exomes 𝑓: 0.0069 (12 hom. 2427 hem.)
• Consequence: GPRASP3 NM_001142524.2 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.66

Genes affected

GPRASP3 (HGNC:29353): (G protein-coupled receptor associated sorting protein family member 3) This gene is a member of a gene family which encodes proteins with a basic helix-loop-helix domain. Other members of this gene family encode proteins which function as transcription factors, either enhancing or inhibiting transcription depending on the activity of other DNA binding proteins. The coding region of this gene is located entirely within the terminal exon. The encoded protein may be involved in the survival of neurons (PMID: 15034937). Multiple alternatively spliced variants, encoding the same protein, have been identified. [provided by RefSeq, Sep 2011]

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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0058374703).
• BP6: Variant X-102749947-T-C is Benign according to our data. Variant chrX-102749947-T-C is described in ClinVar as [Benign]. Clinvar id is 718264.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-102749947-T-C is described in Lovd as [Likely_benign].
• BS2: High Hemizygotes in GnomAd4 at 163 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GPRASP3	NM_001142524.2	c.952T>C	p.Cys318Arg	missense_variant	4/4	ENST00000457056.6
ARMCX5-GPRASP2	NR_146584.3	n.1218+28856T>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GPRASP3	ENST00000457056.6	c.952T>C	p.Cys318Arg	missense_variant	4/4	4	NM_001142524.2	P1
ARMCX5-GPRASP2	ENST00000652409.1	c.952T>C	p.Cys318Arg	missense_variant	8/8			P1

Frequencies

GnomAD3 genomes AF: 0.00488 AC: 547 AN: 112184 Hom.: 1 Cov.: 23 AF XY: 0.00475 AC XY: 163 AN XY: 34348

Gnomad AFR AF: 0.00107

Gnomad AMI AF: 0.00875

Gnomad AMR AF: 0.00197

Gnomad ASJ AF: 0.00566

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00805

Gnomad MID AF: 0.00422

Gnomad NFE AF: 0.00777

Gnomad OTH AF: 0.00528

GnomAD3 exomes AF: 0.00489 AC: 877 AN: 179486 Hom.: 2 AF XY: 0.00457 AC XY: 294 AN XY: 64272

Gnomad AFR exome AF: 0.000993

Gnomad AMR exome AF: 0.00248

Gnomad ASJ exome AF: 0.00607

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000275

Gnomad FIN exome AF: 0.00663

Gnomad NFE exome AF: 0.00776

Gnomad OTH exome AF: 0.00455

GnomAD4 exome AF: 0.00687 AC: 7529 AN: 1095217 Hom.: 12 Cov.: 31 AF XY: 0.00673 AC XY: 2427 AN XY: 360837

Gnomad4 AFR exome AF: 0.000798

Gnomad4 AMR exome AF: 0.00281

Gnomad4 ASJ exome AF: 0.00558

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000224

Gnomad4 FIN exome AF: 0.00706

Gnomad4 NFE exome AF: 0.00797

Gnomad4 OTH exome AF: 0.00644

GnomAD4 genome AF: 0.00487 AC: 547 AN: 112240 Hom.: 1 Cov.: 23 AF XY: 0.00474 AC XY: 163 AN XY: 34414

Gnomad4 AFR AF: 0.00107

Gnomad4 AMR AF: 0.00197

Gnomad4 ASJ AF: 0.00566

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00805

Gnomad4 NFE AF: 0.00778

Gnomad4 OTH AF: 0.00522

Alfa AF: 0.00722 Hom.: 105

Bravo AF: 0.00444

TwinsUK AF: 0.00593 AC: 22

ALSPAC AF: 0.00935 AC: 27

ESP6500AA AF: 0.00104 AC: 4

ESP6500EA AF: 0.00803 AC: 54

ExAC AF: 0.00478 AC: 580

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 31, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.45
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.026	T;T;T;T;T
FATHMM_MKL	Benign	0.61	D
LIST_S2	Benign	0.61	.;.;.;T;.
MetaRNN	Benign	0.0058	T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.9	M;M;M;M;M
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Uncertain	0.65	T
PROVEAN	Uncertain	-3.1	D;D;D;D;D
REVEL	Benign	0.25
Sift	Benign	0.12	T;T;T;T;T
Sift4G	Pathogenic	0.0	D;D;D;D;D
Polyphen		1.0	D;D;D;D;D
Vest4		0.48
MVP		0.38
MPC		0.62
ClinPred		0.027	T
GERP RS		3.5
Varity_R		0.38
gMVP		0.20

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: rs4514179; hg19: chrX-102004875; COSMIC: COSV100772020; COSMIC: COSV100772020;