rs193922098

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM1PM2PM5PP3_Strong

The NM_000033.4(ABCD1):c.838C>A(p.Arg280Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000882 in 113,411 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 Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R280H) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.0000088 ( 0 hom., 0 hem., cov: 26)

Exomes 𝑓: 0.0 ( 0 hom. 0 hem. )

Failed GnomAD Quality Control

Consequence

ABCD1
NM_000033.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 4.46

Publications

10 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 10 ACMG points.

PM1

In a hotspot region, there are 16 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 13 uncertain in NM_000033.4

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chrX-153726105-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 953948.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.965

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
ABCD1	NM_000033.4 link	c.838C>A	p.Arg280Ser	missense_variant	Exon 1 of 10	ENST00000218104.6	NP_000024.2
ABCD1	NM_001440747.1 link	c.838C>A	p.Arg280Ser	missense_variant	Exon 1 of 11		NP_001427676.1
ABCD1	XM_047441917.1 link	c.838C>A	p.Arg280Ser	missense_variant	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.838C>A	p.Arg280Ser	missense_variant	Exon 1 of 10	1	NM_000033.4	ENSP00000218104.3
ABCD1	ENST00000370129.4 link	c.283C>A	p.Arg95Ser	missense_variant	Exon 1 of 2	2		ENSP00000359147.3

Frequencies

GnomAD3 genomes

AF:

0.00000882

AC:

AN:

113357

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000920

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000776

AC:

AN:

128935

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000445

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1067640

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

342512

African (AFR)

AF:

0.00

AC:

AN:

25770

American (AMR)

AF:

0.00

AC:

AN:

31567

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

18200

East Asian (EAS)

AF:

0.00

AC:

AN:

28937

South Asian (SAS)

AF:

0.00

AC:

AN:

49960

European-Finnish (FIN)

AF:

0.00

AC:

AN:

37846

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4063

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

826449

Other (OTH)

AF:

0.00

AC:

AN:

44848

GnomAD4 genome

AF:

0.00000882

AC:

AN:

113411

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

35563

show subpopulations

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

African (AFR)

AF:

0.00

AC:

AN:

31332

American (AMR)

AF:

0.0000919

AC:

AN:

10879

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2659

East Asian (EAS)

AF:

0.00

AC:

AN:

3599

South Asian (SAS)

AF:

0.00

AC:

AN:

2816

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6337

Middle Eastern (MID)

AF:

0.00

AC:

AN:

219

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

53337

Other (OTH)

AF:

0.00

AC:

AN:

1547

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 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: 0.375

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

ExAC

AF:

0.00000842

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.98

BayesDel_addAF

Pathogenic

0.69

BayesDel_noAF

Pathogenic

0.76

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.99

D;D

FATHMM_MKL

Uncertain

0.85

LIST_S2

Uncertain

0.95

D;D

M_CAP

Pathogenic

0.94

MetaRNN

Pathogenic

0.96

D;D

MetaSVM

Pathogenic

0.89

MutationAssessor

Pathogenic

3.5

H;.

PhyloP100

4.5

PrimateAI

Pathogenic

0.83

PROVEAN

Pathogenic

-5.6

D;D

REVEL

Pathogenic

0.97

Sift

Pathogenic

0.0

D;D

Sift4G

Pathogenic

0.0010

D;D

Polyphen

1.0

D;.

Vest4

0.88

MutPred

0.85

Gain of phosphorylation at R280 (P = 0.0389);.;

MVP

1.0

MPC

1.6

ClinPred

0.99

GERP RS

5.1

PromoterAI

0.027

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.99

gMVP

1.0

Mutation Taster

=2/98

disease causing

(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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over