X-153700974-G-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001256447.2(BCAP31):c.704C>T(p.Ala235Val) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. 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. A235T) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 23)
• Consequence: BCAP31 NM_001256447.2 missense, splice_region
• Scores: Splicing: ADA: 0.0002383
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.547

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.032507896).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BCAP31	NM_001256447.2	c.704C>T	p.Ala235Val	missense_variant, splice_region_variant	8/8	ENST00000345046.12
BCAP31	NM_001139457.2	c.905C>T	p.Ala302Val	missense_variant, splice_region_variant	8/8
BCAP31	NM_001139441.1	c.704C>T	p.Ala235Val	missense_variant, splice_region_variant	8/8
BCAP31	NM_005745.8	c.704C>T	p.Ala235Val	missense_variant, splice_region_variant	8/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BCAP31	ENST00000345046.12	c.704C>T	p.Ala235Val	missense_variant, splice_region_variant	8/8	1	NM_001256447.2	P1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 23

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Aug 04, 2023

This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 235 of the BCAP31 protein (p.Ala235Val). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with BCAP31-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The valine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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	0.093
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.57
Cadd	Benign	13
Dann	Benign	0.95
FATHMM_MKL	Benign	0.087	N
LIST_S2	Benign	0.73	T;.;T;T
M_CAP	Benign	0.0079	T
MetaRNN	Benign	0.033	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	0.71	D;D;D
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.84	N;N;.;.
REVEL	Benign	0.033
Sift	Benign	0.17	T;T;.;.
Sift4G	Benign	0.26	T;T;.;.
Polyphen		0.0040	.;B;B;.
Vest4		0.094
MutPred		0.14		.;Gain of methylation at K232 (P = 0.2125);Gain of methylation at K232 (P = 0.2125);.;
MVP		0.61
MPC		0.74
ClinPred		0.062	T
GERP RS		2.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.047
gMVP		0.075

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00024
dbscSNV1_RF	Benign	0.0
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chrX-152966429;