chrX-102749560-A-C

Position:

chrX-102749560-A-C

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_ModerateBP6BS2

The NM_001142524.2(GPRASP3):c.565A>C(p.Asn189His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000174 in 1,209,722 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 60 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N189K) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00011 ( 0 hom., 2 hem., cov: 23)

Exomes 𝑓: 0.00018 ( 0 hom. 58 hem. )

Consequence

GPRASP3
NM_001142524.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:1

Conservation

PhyloP100: -0.386

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 Benign. Variant got -7 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.18488505).

BP6

Variant X-102749560-A-C is Benign according to our data. Variant chrX-102749560-A-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 2661087.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.

BS2

High Hemizygotes in GnomAd4 at 2 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GPRASP3	NM_001142524.2 linkuse as main transcript	c.565A>C	p.Asn189His	missense_variant	4/4	ENST00000457056.6
ARMCX5-GPRASP2	NR_146584.3 linkuse as main transcript	n.1218+28469A>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.565A>C	p.Asn189His	missense_variant	4/4	4	NM_001142524.2	P1
ARMCX5-GPRASP2	ENST00000652409.1 linkuse as main transcript	c.565A>C	p.Asn189His	missense_variant	8/8			P1

Frequencies

GnomAD3 genomes

AF:

0.000108

AC:

AN:

111496

Hom.:

Cov.:

AF XY:

0.0000594

AC XY:

AN XY:

33684

show subpopulations

Gnomad AFR

AF:

0.0000654

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000188

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000131

AC:

AN:

183496

Hom.:

AF XY:

0.0000736

AC XY:

AN XY:

67938

show subpopulations

Gnomad AFR exome

AF:

0.0000760

Gnomad AMR exome

AF:

0.0000365

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000268

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000180

AC:

198

AN:

1098226

Hom.:

Cov.:

AF XY:

0.000160

AC XY:

AN XY:

363582

show subpopulations

Gnomad4 AFR exome

AF:

0.0000379

Gnomad4 AMR exome

AF:

0.0000284

Gnomad4 ASJ exome

AF:

0.0000516

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000221

Gnomad4 OTH exome

AF:

0.000195

GnomAD4 genome

AF:

0.000108

AC:

AN:

111496

Hom.:

Cov.:

AF XY:

0.0000594

AC XY:

AN XY:

33684

show subpopulations

Gnomad4 AFR

AF:

0.0000654

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000188

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000218

Hom.:

Bravo

AF:

0.000181

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000297

AC:

ExAC

AF:

0.000115

AC:

EpiCase

AF:

0.000164

EpiControl

AF:

0.000356

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 30, 2022

The c.565A>C (p.N189H) 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 565, causing the asparagine (N) at amino acid position 189 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Mar 01, 2023

GPRASP3: BP4, BS2 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.66

BayesDel_noAF

Benign

-0.88

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.13

T;T;T;T;T

FATHMM_MKL

Benign

0.43

LIST_S2

Benign

0.67

.;.;.;T;.

M_CAP

Benign

0.0031

MetaRNN

Benign

0.18

T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.7

M;M;M;M;M

MutationTaster

Benign

1.0

N;N;N;N;N

PrimateAI

Benign

0.38

PROVEAN

Uncertain

-2.7

D;D;D;D;D

REVEL

Benign

0.092

Sift

Uncertain

0.0070

D;D;D;D;D

Sift4G

Uncertain

0.013

D;D;D;D;D

Polyphen

0.92

P;P;P;P;P

Vest4

0.16

MVP

0.61

MPC

0.37

ClinPred

0.14

GERP RS

-1.8

Varity_R

0.20

gMVP

0.22

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