chrX-153725559-C-A

Variant names:

• chrX-153725559-C-A
• rs1557052294
• NM_000033.4:c.293C>A

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_000033.4(ABCD1):​c.293C>A​(p.Ser98*) variant causes a stop gained change. The variant allele was found at a frequency of 0.000000937 in 1,067,767 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. S98S) has been classified as Uncertain significance. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 26)
  • Exomes 𝑓: 9.4e-7 (0 hom. 0 hem.)
• Consequence: ABCD1 NM_000033.4 stop_gained
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 5.70
• Publications: 0 publications found

Genes affected

ABCD1 (HGNC:61): (ATP binding cassette subfamily D member 1) The protein encoded by this gene is a member of the superfamily of ATP-binding cassette (ABC) transporters. ABC proteins transport various molecules across extra- and intra-cellular membranes. ABC genes are divided into seven distinct subfamilies (ABC1, MDR/TAP, MRP, ALD, OABP, GCN20, White). This protein is a member of the ALD subfamily, which is involved in peroxisomal import of fatty acids and/or fatty acyl-CoAs in the organelle. All known peroxisomal ABC transporters are half transporters which require a partner half transporter molecule to form a functional homodimeric or heterodimeric transporter. This peroxisomal membrane protein is likely involved in the peroxisomal transport or catabolism of very long chain fatty acids. Defects in this gene have been identified as the underlying cause of adrenoleukodystrophy, an X-chromosome recessively inherited demyelinating disorder of the nervous system. [provided by RefSeq, Jul 2008]

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

ACMG classification

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-153725559-C-A is Pathogenic according to our data. Variant chrX-153725559-C-A is described in ClinVar as Pathogenic. ClinVar VariationId is 2737401.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000033.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ABCD1	NM_000033.4	MANE Select	c.293C>A	p.Ser98*	stop_gained	Exon 1 of 10	NP_000024.2
	ABCD1	NM_001440747.1		c.293C>A	p.Ser98*	stop_gained	Exon 1 of 11	NP_001427676.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ABCD1	ENST00000218104.6	TSL:1 MANE Select	c.293C>A	p.Ser98*	stop_gained	Exon 1 of 10	ENSP00000218104.3	P33897
	ABCD1	ENST00000862307.1		c.293C>A	p.Ser98*	stop_gained	Exon 1 of 11	ENSP00000532366.1
	ABCD1	ENST00000862306.1		c.293C>A	p.Ser98*	stop_gained	Exon 1 of 11	ENSP00000532365.1

Frequencies

GnomAD3 genomes Cov.: 26

GnomAD4 exome AF: 9.37e-7 AC: 1 AN: 1067767 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 343159

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 25894

American (AMR) AF: 0.00 AC: 0 AN: 33362

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 17758

East Asian (EAS) AF: 0.00 AC: 0 AN: 29547

South Asian (SAS) AF: 0.00 AC: 0 AN: 49877

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 36645

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3819

European-Non Finnish (NFE) AF: 0.00000121 AC: 1 AN: 826069

Other (OTH) AF: 0.00 AC: 0 AN: 44796

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 26

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Adrenoleukodystrophy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.74	D
BayesDel_noAF	Pathogenic	0.52
CADD	Pathogenic	36
DANN	Uncertain	0.99
FATHMM_MKL	Uncertain	0.95	D
PhyloP100		5.7
Vest4		0.82
GERP RS		5.3
PromoterAI		-0.0075	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=1/199	disease causing (fs/PTC)

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: rs1557052294; hg19: chrX-152991014;