X-102749943-G-T

Variant names:

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_001142524.2(GPRASP3):c.948G>T(p.Met316Ile) variant causes a missense change. The variant allele was found at a frequency of 0.0000422 in 1,207,992 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 15 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000036 ( 0 hom., 3 hem., cov: 23)

Exomes 𝑓: 0.000043 ( 0 hom. 12 hem. )

Consequence

GPRASP3
NM_001142524.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.73

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 -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.1857889).

BS2

High Hemizygotes in GnomAd4 at 3 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GPRASP3	NM_001142524.2 link	c.948G>T	p.Met316Ile	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.948G>T	p.Met316Ile	missense_variant	Exon 4 of 4	4	NM_001142524.2	ENSP00000403226.1		Q6PI77
ARMCX5-GPRASP2	ENST00000652409.1 link	c.948G>T	p.Met316Ile	missense_variant	Exon 8 of 8			ENSP00000498643.1

Frequencies

GnomAD3 genomes

AF:

0.0000357

AC:

AN:

112112

Hom.:

Cov.:

AF XY:

0.0000875

AC XY:

AN XY:

34274

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000188

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:

0.0000376

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000223

AC:

AN:

179661

Hom.:

AF XY:

0.0000155

AC XY:

AN XY:

64433

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000496

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000429

AC:

AN:

1095880

Hom.:

Cov.:

AF XY:

0.0000332

AC XY:

AN XY:

361462

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:

0.0000559

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000357

AC:

AN:

112112

Hom.:

Cov.:

AF XY:

0.0000875

AC XY:

AN XY:

34274

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000188

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000376

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000434

Hom.:

Bravo

AF:

0.0000604

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Feb 28, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.948G>T (p.M316I) alteration is located in exon 4 (coding exon 1) of the BHLHB9 gene. This alteration results from a G to T substitution at nucleotide position 948, causing the methionine (M) at amino acid position 316 to be replaced by an isoleucine (I). 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

Uncertain

0.48

BayesDel_addAF

Benign

-0.31

BayesDel_noAF

Benign

-0.53

CADD

Benign

DANN

Benign

0.92

DEOGEN2

Benign

0.011

T;T;T;T;T

FATHMM_MKL

Uncertain

0.82

LIST_S2

Benign

0.59

.;.;.;T;.

M_CAP

Benign

0.042

MetaRNN

Benign

0.19

T;T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.9

M;M;M;M;M

PrimateAI

Uncertain

0.58

PROVEAN

Benign

-1.3

N;N;N;N;N

REVEL

Benign

0.053

Sift

Benign

0.51

T;T;T;T;T

Sift4G

Uncertain

0.039

D;D;D;D;D

Polyphen

0.63

P;P;P;P;P

Vest4

0.35

MutPred

0.39

Gain of ubiquitination at K315 (P = 0.1245);Gain of ubiquitination at K315 (P = 0.1245);Gain of ubiquitination at K315 (P = 0.1245);Gain of ubiquitination at K315 (P = 0.1245);Gain of ubiquitination at K315 (P = 0.1245);

MVP

0.54

MPC

0.11

ClinPred

0.18

GERP RS

4.7

Varity_R

0.28

gMVP

0.21

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