rs1057518852

Variant names:

• chrX-153720946-A-G
• rs1057518852
• NM_001256447.2:c.119T>C

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_001256447.2(BCAP31):​c.119T>C​(p.Leu40Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L40M) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 23)
• Consequence: BCAP31 NM_001256447.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 8.03
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• severe motor and intellectual disabilities-sensorineural deafness-dystonia syndrome

  Inheritance: XL, AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, PanelApp Australia, G2P, Labcorp Genetics (formerly Invitae), Orphanet

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.96

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BCAP31	NM_001256447.2	c.119T>C	p.Leu40Pro	missense_variant	Exon 3 of 8	ENST00000345046.12	NP_001243376.1
BCAP31	NM_001139457.2	c.320T>C	p.Leu107Pro	missense_variant	Exon 3 of 8		NP_001132929.1
BCAP31	NM_001139441.1	c.119T>C	p.Leu40Pro	missense_variant	Exon 3 of 8		NP_001132913.1
BCAP31	NM_005745.8	c.119T>C	p.Leu40Pro	missense_variant	Exon 3 of 8		NP_005736.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BCAP31	ENST00000345046.12	c.119T>C	p.Leu40Pro	missense_variant	Exon 3 of 8	1	NM_001256447.2	ENSP00000343458.6

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 23

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Seizure;C0557874:Global developmental delay Uncertain:1

Jan 27, 2015

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Inborn genetic diseases Uncertain:1

Sep 06, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.320T>C (p.L107P) alteration is located in exon 3 (coding exon 3) of the BCAP31 gene. This alteration results from a T to C substitution at nucleotide position 320, causing the leucine (L) at amino acid position 107 to be replaced by a proline (P). 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	0.42
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.56
CADD	Pathogenic	26
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.52	.;D;D;.;T;.;T;.;T
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.84	T;.;T;T;D;D;D;D;T
M_CAP	Uncertain	0.27	D
MetaRNN	Pathogenic	0.96	D;D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.31	T
MutationAssessor	Uncertain	2.1	.;M;M;.;.;.;.;.;.
PhyloP100		8.0
PrimateAI	Uncertain	0.72	T
PROVEAN	Pathogenic	-5.0	D;D;.;.;D;D;D;D;D
REVEL	Pathogenic	0.79
Sift	Uncertain	0.0020	D;D;.;.;D;D;D;D;D
Sift4G	Uncertain	0.0020	D;D;.;.;.;D;D;.;.
Polyphen		1.0	.;D;D;.;.;.;.;.;.
Vest4		0.77
MutPred		0.81		.;Loss of helix (P = 0.0068);Loss of helix (P = 0.0068);Loss of helix (P = 0.0068);Loss of helix (P = 0.0068);Loss of helix (P = 0.0068);Loss of helix (P = 0.0068);Loss of helix (P = 0.0068);Loss of helix (P = 0.0068);
MVP		0.96
MPC		2.3
ClinPred		1.0	D
GERP RS		5.8
Varity_R		0.96
gMVP		0.97
Mutation Taster		=12/88	disease causing

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

Other links and lift over

dbSNP: rs1057518852; hg19: chrX-152986401;