rs782628755

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM1PM2PP3_Moderate

The NM_000033.4(ABCD1):c.249C>A(p.Phe83Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000259 in 1,159,155 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. F83F) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0000088 ( 0 hom., 1 hem., cov: 25)

Exomes 𝑓: 0.0000019 ( 0 hom. 0 hem. )

Consequence

ABCD1
NM_000033.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.13

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: Likely_pathogenic. The variant received 6 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 12 uncertain in NM_000033.4

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.859

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
ABCD1	NM_000033.4 link	c.249C>A	p.Phe83Leu	missense_variant	Exon 1 of 10	ENST00000218104.6	NP_000024.2
ABCD1	NM_001440747.1 link	c.249C>A	p.Phe83Leu	missense_variant	Exon 1 of 11		NP_001427676.1
ABCD1	XM_047441917.1 link	c.249C>A	p.Phe83Leu	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.249C>A	p.Phe83Leu	missense_variant	Exon 1 of 10	1	NM_000033.4	ENSP00000218104.3

Frequencies

GnomAD3 genomes

AF:

0.00000884

AC:

AN:

113152

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000357

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000191

AC:

AN:

1046003

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

330659

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:

25131

American (AMR)

AF:

0.00

AC:

AN:

29390

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

17307

East Asian (EAS)

AF:

0.00

AC:

AN:

28307

South Asian (SAS)

AF:

0.00

AC:

AN:

47610

European-Finnish (FIN)

AF:

0.00

AC:

AN:

34818

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3111

European-Non Finnish (NFE)

AF:

0.00000245

AC:

AN:

816468

Other (OTH)

AF:

0.00

AC:

AN:

43861

⚠️ 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: 0.250

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

AF:

0.00000884

AC:

AN:

113152

Hom.:

Cov.:

AF XY:

0.0000283

AC XY:

AN XY:

35308

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31240

American (AMR)

AF:

0.00

AC:

AN:

10867

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2656

East Asian (EAS)

AF:

0.00

AC:

AN:

3580

South Asian (SAS)

AF:

0.000357

AC:

AN:

2805

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6316

Middle Eastern (MID)

AF:

0.00

AC:

AN:

240

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

53238

Other (OTH)

AF:

0.00

AC:

AN:

1529

Age Distribution

Genome Hom

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

Alfa

AF:

0.00

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.84

BayesDel_addAF

Pathogenic

0.34

BayesDel_noAF

Pathogenic

0.25

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.67

FATHMM_MKL

Uncertain

0.92

LIST_S2

Benign

0.76

M_CAP

Pathogenic

0.75

MetaRNN

Pathogenic

0.86

MetaSVM

Pathogenic

1.0

MutationAssessor

Benign

0.97

PhyloP100

1.1

PrimateAI

Pathogenic

0.86

PROVEAN

Benign

-0.12

REVEL

Pathogenic

0.68

Sift

Benign

0.17

Sift4G

Benign

0.20

Vest4

0.69

ClinPred

0.69

GERP RS

3.3

PromoterAI

0.0010

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.8

Varity_R

0.28

gMVP

0.96

Mutation Taster

=43/57

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

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over