X-102750143-A-C

Position:

chrX-102750143-A-C

Variant summary

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

The NM_001142524.2(GPRASP3):c.1148A>C(p.Lys383Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000132 in 1,208,849 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. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000089 ( 0 hom., 0 hem., cov: 24)

Exomes 𝑓: 0.000014 ( 0 hom. 1 hem. )

Consequence

GPRASP3
NM_001142524.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.13

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:

Genome browser will be placed here

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=0.026699305).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GPRASP3	NM_001142524.2 linkuse as main transcript	c.1148A>C	p.Lys383Thr	missense_variant	4/4	ENST00000457056.6
ARMCX5-GPRASP2	NR_146584.3 linkuse as main transcript	n.1218+29052A>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GPRASP3	ENST00000457056.6 linkuse as main transcript	c.1148A>C	p.Lys383Thr	missense_variant	4/4	4	NM_001142524.2	P1
ARMCX5-GPRASP2	ENST00000652409.1 linkuse as main transcript	c.1148A>C	p.Lys383Thr	missense_variant	8/8			P1

Frequencies

GnomAD3 genomes

AF:

0.00000892

AC:

AN:

112102

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

34244

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000279

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000941

AC:

AN:

180618

Hom.:

AF XY:

0.0000612

AC XY:

AN XY:

65324

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00124

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000137

AC:

AN:

1096747

Hom.:

Cov.:

AF XY:

0.00000276

AC XY:

AN XY:

362219

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000497

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000892

AC:

AN:

112102

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

34244

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000279

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000378

ExAC

AF:

0.0000988

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 13, 2022

The c.1148A>C (p.K383T) alteration is located in exon 4 (coding exon 1) of the BHLHB9 gene. This alteration results from a A to C substitution at nucleotide position 1148, causing the lysine (K) at amino acid position 383 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.18

BayesDel_addAF

Benign

-0.61

BayesDel_noAF

Benign

-0.69

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.0079

T;T;T;T;T

FATHMM_MKL

Benign

0.40

LIST_S2

Benign

0.61

.;.;.;T;.

M_CAP

Benign

0.0044

MetaRNN

Benign

0.027

T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.38

N;N;N;N;N

MutationTaster

Benign

0.99

N;N;N;N;N

PrimateAI

Uncertain

0.52

PROVEAN

Benign

0.060

N;N;N;N;N

REVEL

Benign

0.020

Sift

Benign

0.47

T;T;T;T;T

Sift4G

Pathogenic

0.0

D;D;D;D;D

Polyphen

0.16

B;B;B;B;B

Vest4

0.20

MutPred

0.45

Loss of methylation at K383 (P = 0.0067);Loss of methylation at K383 (P = 0.0067);Loss of methylation at K383 (P = 0.0067);Loss of methylation at K383 (P = 0.0067);Loss of methylation at K383 (P = 0.0067);

MVP

0.28

MPC

0.16

ClinPred

0.040

GERP RS

1.7

Varity_R

0.056

gMVP

0.33

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