rs111450526

chrX-153704053-G-A

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_001256447.2(BCAP31):c.383C>T(p.Thr128Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00182 in 1,209,172 control chromosomes in the GnomAD database, including 1 homozygotes. There are 697 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). Synonymous variant affecting the same amino acid position (i.e. T128T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0014 (0 hom., 50 hem., cov: 24)
  • Exomes 𝑓: 0.0019 (1 hom. 647 hem.)
• Consequence: BCAP31 NM_001256447.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:6
• Conservation: PhyloP100: 7.61

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]

ACMG classification

Verdict is Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.022595048).
• BP6: Variant X-153704053-G-A is Benign according to our data. Variant chrX-153704053-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 235341.We mark this variant Likely_benign, oryginal submissions are: {Benign=2, Uncertain_significance=1, Likely_benign=2}. Variant chrX-153704053-G-A is described in Lovd as [Likely_benign].
• BS2: High Hemizygotes in GnomAd at 50 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BCAP31	NM_001256447.2	c.383C>T	p.Thr128Met	missense_variant	5/8	ENST00000345046.12
BCAP31	NM_001139457.2	c.584C>T	p.Thr195Met	missense_variant	5/8
BCAP31	NM_001139441.1	c.383C>T	p.Thr128Met	missense_variant	5/8
BCAP31	NM_005745.8	c.383C>T	p.Thr128Met	missense_variant	5/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BCAP31	ENST00000345046.12	c.383C>T	p.Thr128Met	missense_variant	5/8	1	NM_001256447.2	P1

Frequencies

GnomAD3 genomes AF: 0.00137 AC: 154 AN: 112483 Hom.: 0 Cov.: 24 AF XY: 0.00144 AC XY: 50 AN XY: 34641

Gnomad AFR AF: 0.000323

Gnomad AMI AF: 0.00438

Gnomad AMR AF: 0.00235

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000490

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00204

Gnomad OTH AF: 0.00267

GnomAD3 exomes AF: 0.00138 AC: 253 AN: 183054 Hom.: 0 AF XY: 0.00136 AC XY: 92 AN XY: 67502

Gnomad AFR exome AF: 0.000304

Gnomad AMR exome AF: 0.00117

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000433

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000255

Gnomad NFE exome AF: 0.00246

Gnomad OTH exome AF: 0.00133

GnomAD4 exome AF: 0.00187 AC: 2046 AN: 1096636 Hom.: 1 Cov.: 30 AF XY: 0.00179 AC XY: 647 AN XY: 362056

Gnomad4 AFR exome AF: 0.000265

Gnomad4 AMR exome AF: 0.00128

Gnomad4 ASJ exome AF: 0.0000516

Gnomad4 EAS exome AF: 0.000199

Gnomad4 SAS exome AF: 0.0000370

Gnomad4 FIN exome AF: 0.000198

Gnomad4 NFE exome AF: 0.00228

Gnomad4 OTH exome AF: 0.00126

GnomAD4 genome AF: 0.00137 AC: 154 AN: 112536 Hom.: 0 Cov.: 24 AF XY: 0.00144 AC XY: 50 AN XY: 34704

Gnomad4 AFR AF: 0.000322

Gnomad4 AMR AF: 0.00235

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000490

Gnomad4 NFE AF: 0.00204

Gnomad4 OTH AF: 0.00264

Alfa AF: 0.00204 Hom.: 29

Bravo AF: 0.00151

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.00242 AC: 7

ESP6500AA AF: 0.000261 AC: 1

ESP6500EA AF: 0.00163 AC: 11

ExAC AF: 0.00135 AC: 164

EpiCase AF: 0.00213

EpiControl AF: 0.00267

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:6

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:5

Benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	May 10, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 26, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2017	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 14, 2021	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

BCAP31-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 23, 2020

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.11
Cadd	Uncertain	25
Dann	Pathogenic	1.0
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Uncertain	0.93	D;.;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.41	D
MetaRNN	Benign	0.023	T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.49	T
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	-2.1	N;N;.;.;N;N;N;N;N
REVEL	Uncertain	0.44
Sift	Uncertain	0.011	D;D;.;.;D;D;D;D;D
Sift4G	Benign	0.091	T;D;.;.;.;D;D;.;.
Polyphen		0.99	.;D;D;.;.;.;.;.;.
Vest4		0.34
MVP		0.64
MPC		1.8
ClinPred		0.042	T
GERP RS		4.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.14
gMVP		0.49

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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

Other links and lift over

dbSNP: rs111450526; hg19: chrX-152969508;