Genetic Variant NM_001142524.2:c.766G>C (chrX-102749761-G-C) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001142524.2(GPRASP3):c.766G>C(p.Ala256Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000182 in 1,098,170 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 23)

Exomes 𝑓: 0.0000018 ( 0 hom. 1 hem. )

Consequence

GPRASP3
NM_001142524.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.521

Variant links:

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]

GPRASP3 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 Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.05131498).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GPRASP3	NM_001142524.2 link	c.766G>C	p.Ala256Pro	missense_variant	Exon 4 of 4	ENST00000457056.6	NP_001135996.1	Q6PI77

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GPRASP3	ENST00000457056.6 link	c.766G>C	p.Ala256Pro	missense_variant	Exon 4 of 4	4	NM_001142524.2	ENSP00000403226.1		Q6PI77
ARMCX5-GPRASP2	ENST00000652409.1 link	c.766G>C	p.Ala256Pro	missense_variant	Exon 8 of 8			ENSP00000498643.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000182

AC:

AN:

1098170

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

363528

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000237

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.083

BayesDel_addAF

Benign

-0.56

BayesDel_noAF

Benign

-1.0

CADD

Benign

0.38

DANN

Benign

0.90

DEOGEN2

Benign

0.024

T;T;T;T;T

FATHMM_MKL

Benign

0.0096

LIST_S2

Benign

0.57

.;.;.;T;.

M_CAP

Benign

0.0018

MetaRNN

Benign

0.051

T;T;T;T;T

MetaSVM

Benign

-0.99

MutationAssessor

Benign

1.2

L;L;L;L;L

PrimateAI

Benign

0.26

PROVEAN

Benign

-0.94

N;N;N;N;N

REVEL

Benign

0.018

Sift

Benign

0.24

T;T;T;T;T

Sift4G

Uncertain

0.021

D;D;D;D;D

Polyphen

0.0010

B;B;B;B;B

Vest4

0.056

MutPred

0.23

Gain of catalytic residue at A256 (P = 0.0045);Gain of catalytic residue at A256 (P = 0.0045);Gain of catalytic residue at A256 (P = 0.0045);Gain of catalytic residue at A256 (P = 0.0045);Gain of catalytic residue at A256 (P = 0.0045);

MVP

0.085

MPC

0.11

ClinPred

0.11

GERP RS

-8.0

Varity_R

0.12

gMVP

0.27

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

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over