rs1557052294

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1PM2PP5_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

Scores

Clinical Significance

Pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 5.70

Publications

0 publications found

Variant links:

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]

ABCD1 Gene-Disease associations (from GenCC):

adrenoleukodystrophy
Inheritance: XL Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, G2P
X-linked cerebral adrenoleukodystrophy
Inheritance: XL Classification: DEFINITIVE, SUPPORTIVE Submitted by: Laboratory for Molecular Medicine, Orphanet
hereditary spastic paraplegia
Inheritance: XL Classification: STRONG Submitted by: Genomics England PanelApp
Hirschsprung disease
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
adrenomyeloneuropathy
Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet

ABCD1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
ABCD1	NM_000033.4 link	c.293C>A	p.Ser98*	stop_gained	Exon 1 of 10	ENST00000218104.6	NP_000024.2
ABCD1	NM_001440747.1 link	c.293C>A	p.Ser98*	stop_gained	Exon 1 of 11		NP_001427676.1
ABCD1	XM_047441917.1 link	c.293C>A	p.Ser98*	stop_gained	Exon 1 of 8		XP_047297873.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ABCD1	ENST00000218104.6 link	c.293C>A	p.Ser98*	stop_gained	Exon 1 of 10	1	NM_000033.4	ENSP00000218104.3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

9.37e-7

AC:

AN:

1067767

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

343159

show subpopulations

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

African (AFR)

AF:

0.00

AC:

AN:

25894

American (AMR)

AF:

0.00

AC:

AN:

33362

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

17758

East Asian (EAS)

AF:

0.00

AC:

AN:

29547

South Asian (SAS)

AF:

0.00

AC:

AN:

49877

European-Finnish (FIN)

AF:

0.00

AC:

AN:

36645

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3819

European-Non Finnish (NFE)

AF:

0.00000121

AC:

AN:

826069

Other (OTH)

AF:

0.00

AC:

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.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.325

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Adrenoleukodystrophy

Pathogenic:1

May 27, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

For these reasons, this variant has been classified as Pathogenic. This premature translational stop signal has been observed in individual(s) with ABCD1-related conditions (PMID: 23419472). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Ser98*) in the ABCD1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ABCD1 are known to be pathogenic (PMID: 11748843).

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.74

BayesDel_noAF

Pathogenic

0.52

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

PhyloP100

5.7

Vest4

0.82

GERP RS

5.3

PromoterAI

-0.0075

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Mutation Taster

=1/199

disease causing (fs/PTC)

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over