rs782683945

chrX-153703019-C-A

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_Strong BP6

The NM_001256447.2(BCAP31):c.517G>T(p.Ala173Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000821 in 1,096,385 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 25)
  • Exomes 𝑓: 0.0000082 (0 hom. 1 hem.)
• Consequence: BCAP31 NM_001256447.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: -1.43

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 -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.043188393).
• BP6: Variant X-153703019-C-A is Benign according to our data. Variant chrX-153703019-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 599439.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BCAP31	NM_001256447.2	c.517G>T	p.Ala173Ser	missense_variant	6/8	ENST00000345046.12
BCAP31	NM_001139457.2	c.718G>T	p.Ala240Ser	missense_variant	6/8
BCAP31	NM_001139441.1	c.517G>T	p.Ala173Ser	missense_variant	6/8
BCAP31	NM_005745.8	c.517G>T	p.Ala173Ser	missense_variant	6/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BCAP31	ENST00000345046.12	c.517G>T	p.Ala173Ser	missense_variant	6/8	1	NM_001256447.2	P1

Frequencies

GnomAD3 genomes Cov.: 25

GnomAD3 exomes AF: 0.0000383 AC: 7 AN: 182741 Hom.: 0 AF XY: 0.0000148 AC XY: 1 AN XY: 67355

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000255

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000821 AC: 9 AN: 1096385 Hom.: 0 Cov.: 31 AF XY: 0.00000276 AC XY: 1 AN XY: 362741

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000256

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 25

Bravo AF: 0.00000756

ExAC AF: 0.0000247 AC: 3

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Oct 11, 2023

This sequence change replaces alanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 173 of the BCAP31 protein (p.Ala173Ser). This variant is present in population databases (rs782683945, gnomAD 0.03%). This variant has not been reported in the literature in individuals affected with BCAP31-related conditions. ClinVar contains an entry for this variant (Variation ID: 599439). 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 serine 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. -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Institute for Genomic Medicine (IGM) Clinical Laboratory, Nationwide Children's Hospital

Nov 20, 2017

BS2, BP4, BP5; This alteration was seen in a healthy adult where full penetrance of the disorder is expected at an early age, is predicted to be tolerated by multiple functional prediction tools, and was found in a case with an alternate molecular basis for disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.072
BayesDel_addAF	Benign	-0.70	T
BayesDel_noAF	Benign	-0.95
Cadd	Benign	0.043
Dann	Benign	0.68
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.57	T;.;T;T;T;T;T
M_CAP	Benign	0.0080	T
MetaRNN	Benign	0.043	T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.28	T
PROVEAN	Benign	0.51	N;N;.;N;N;N;N
REVEL	Benign	0.0080
Sift	Benign	0.28	T;T;.;T;T;T;T
Sift4G	Benign	0.52	T;T;.;.;T;T;.
Polyphen		0.0	.;B;B;.;.;.;.
Vest4		0.047
MutPred		0.33		.;Gain of phosphorylation at A173 (P = 0.0283);Gain of phosphorylation at A173 (P = 0.0283);Gain of phosphorylation at A173 (P = 0.0283);Gain of phosphorylation at A173 (P = 0.0283);Gain of phosphorylation at A173 (P = 0.0283);Gain of phosphorylation at A173 (P = 0.0283);
MVP		0.42
MPC		0.68
ClinPred		0.0090	T
GERP RS		-1.1
Varity_R		0.13
gMVP		0.12

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

Other links and lift over

dbSNP: rs782683945; hg19: chrX-152968474;