X-153700962-C-T

Position:

chrX-153700962-C-T

Variant summary

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

The NM_001256447.2(BCAP31):c.716G>A(p.Gly239Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000913 in 1,205,017 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 4 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.0000090 ( 0 hom., 1 hem., cov: 23)

Exomes 𝑓: 0.0000091 ( 0 hom. 3 hem. )

Consequence

BCAP31
NM_001256447.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 1.56

Variant links:

Genes affected

BCAP31 (HGNC:16695): (B cell receptor associated protein 31) This gene encodes a member of the B-cell receptor associated protein 31 superfamily. The encoded protein is a multi-pass transmembrane protein of the endoplasmic reticulum that is involved in the anterograde transport of membrane proteins from the endoplasmic reticulum to the Golgi and in caspase 8-mediated apoptosis. Microdeletions in this gene are associated with contiguous ABCD1/DXS1375E deletion syndrome (CADDS), a neonatal disorder. Alternative splicing of this gene results in multiple transcript variants. Two related pseudogenes have been identified on chromosome 16. [provided by RefSeq, Jan 2012]

BCAP31 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=0.117408276).

BS2

High Hemizygotes in GnomAdExome4 at 3 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
BCAP31	NM_001256447.2 linkuse as main transcript	c.716G>A	p.Gly239Asp	missense_variant	8/8	ENST00000345046.12
BCAP31	NM_001139457.2 linkuse as main transcript	c.917G>A	p.Gly306Asp	missense_variant	8/8
BCAP31	NM_001139441.1 linkuse as main transcript	c.716G>A	p.Gly239Asp	missense_variant	8/8
BCAP31	NM_005745.8 linkuse as main transcript	c.716G>A	p.Gly239Asp	missense_variant	8/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BCAP31	ENST00000345046.12 linkuse as main transcript	c.716G>A	p.Gly239Asp	missense_variant	8/8	1	NM_001256447.2	P1	P51572-1

Frequencies

GnomAD3 genomes

AF:

0.00000898

AC:

AN:

111369

Hom.:

Cov.:

AF XY:

0.0000298

AC XY:

AN XY:

33581

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:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000189

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000574

AC:

AN:

174163

Hom.:

AF XY:

0.00

AC XY:

AN XY:

60041

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:

0.0000128

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000914

AC:

AN:

1093648

Hom.:

Cov.:

AF XY:

0.00000834

AC XY:

AN XY:

359838

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:

0.0000107

Gnomad4 OTH exome

AF:

0.0000218

GnomAD4 genome

AF:

0.00000898

AC:

AN:

111369

Hom.:

Cov.:

AF XY:

0.0000298

AC XY:

AN XY:

33581

show subpopulations

Gnomad4 AFR

AF:

0.00

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:

0.0000189

Gnomad4 OTH

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Severe motor and intellectual disabilities-sensorineural deafness-dystonia syndrome

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory of genome editing, Research Centre for Medical Genetics	Sep 22, 2023	PM2, PP1, PP3 -
Uncertain significance, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Dec 20, 2023	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3B. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with deafness, dystonia, and cerebral hypomyelination, (MIM#300475). (I) 0109 - This gene is associated with X-linked recessive disease. Heterozygous females are both asymptomatic, or affected with hearing loss, intellectual disability and/or liver disease (PMID: 33603160). (I) 0200 - Variant is predicted to result in a missense amino acid change from glycine to aspartic acid. (I) 0253 - This variant is hemizygous. (I) 0304 - Variant is present in gnomAD (v2, v3) <0.01 (1 heterozygote, 0 homozygotes, 1 hemizygote). (SP) 0503 - Missense variant consistently predicted to be tolerated by multiple in silico tools or not conserved in placental mammals with a minor amino acid change. (SB) 0600 - Variant is located in the annotated Bap31_Bap29_C domain (NCBI conserved domain). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0809 - Previous evidence of pathogenicity for this variant is inconclusive. This variant has been reported as a VUS (ClinVar), observed in an individual with movement disorders (Westmead), and maternally inherited in a hemizygous individual with delayed motor development, hearing loss, microcephaly and dysmorphic features (PMID: 35887114). (I) 1007 - No published functional evidence has been identified for this variant. (I) 1205 - This variant has been shown to be maternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Oct 04, 2023

This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 239 of the BCAP31 protein (p.Gly239Asp). This variant is present in population databases (no rsID available, gnomAD 0.001%). This missense change has been observed in individual(s) with BCAP31-related conditions (PMID: 35887114). ClinVar contains an entry for this variant (Variation ID: 1347813). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant¬†is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.21

BayesDel_addAF

Benign

-0.066

BayesDel_noAF

Benign

-0.33

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.11

.;T;T;.

FATHMM_MKL

Benign

0.13

LIST_S2

Benign

0.80

T;.;T;T

M_CAP

Benign

0.024

MetaRNN

Benign

0.12

T;T;T;T

MetaSVM

Benign

-0.96

MutationAssessor

Benign

1.3

.;L;L;.

MutationTaster

Benign

0.97

D;D;N

PrimateAI

Uncertain

0.48

PROVEAN

Benign

-0.87

N;N;.;.

REVEL

Benign

0.18

Sift

Benign

0.068

T;T;.;.

Sift4G

Benign

0.12

T;T;.;.

Polyphen

0.66

.;P;P;.

Vest4

0.33

MutPred

0.16

.;Gain of methylation at K243 (P = 0.1162);Gain of methylation at K243 (P = 0.1162);.;

MVP

0.59

MPC

1.0

ClinPred

0.22

GERP RS

3.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.16

gMVP

0.10

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