rs200849757

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 2P and 6B. PM1BP4BP6BS2

The NM_000033.4(ABCD1):c.756C>A(p.Phe252Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000115 in 1,204,541 control chromosomes in the GnomAD database, including 1 homozygotes. There are 42 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

Frequency

Genomes: 𝑓 0.000018 ( 0 hom., 1 hem., cov: 26)

Exomes 𝑓: 0.00013 ( 1 hom. 41 hem. )

Consequence

ABCD1
NM_000033.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:1

Conservation

PhyloP100: -0.182

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_benign. The variant received -4 ACMG points.

PM1

In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 12 uncertain in NM_000033.4

BP4

Computational evidence support a benign effect (MetaRNN=0.31499016).

BP6

Variant X-153726022-C-A is Benign according to our data. Variant chrX-153726022-C-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 562209.

BS2

High AC in GnomAdExome4 at 137 XL,AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
ABCD1	NM_000033.4 link	c.756C>A	p.Phe252Leu	missense_variant	Exon 1 of 10	ENST00000218104.6	NP_000024.2
ABCD1	NM_001440747.1 link	c.756C>A	p.Phe252Leu	missense_variant	Exon 1 of 11		NP_001427676.1
ABCD1	XM_047441917.1 link	c.756C>A	p.Phe252Leu	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.756C>A	p.Phe252Leu	missense_variant	Exon 1 of 10	1	NM_000033.4	ENSP00000218104.3
ABCD1	ENST00000370129.4 link	c.201C>A	p.Phe67Leu	missense_variant	Exon 1 of 2	2		ENSP00000359147.3

Frequencies

GnomAD3 genomes

AF:

0.0000176

AC:

AN:

113868

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:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000374

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000116

AC:

AN:

172658

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000263

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000126

AC:

137

AN:

1090620

Hom.:

Cov.:

AF XY:

0.000115

AC XY:

AN XY:

357694

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26254

American (AMR)

AF:

0.00

AC:

AN:

34776

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19039

East Asian (EAS)

AF:

0.00

AC:

AN:

30026

South Asian (SAS)

AF:

0.00

AC:

AN:

53503

European-Finnish (FIN)

AF:

0.00

AC:

AN:

39186

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4108

European-Non Finnish (NFE)

AF:

0.000161

AC:

135

AN:

837967

Other (OTH)

AF:

0.0000437

AC:

AN:

45761

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome 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

GnomAD4 genome

AF:

0.0000176

AC:

AN:

113921

Hom.:

Cov.:

AF XY:

0.0000277

AC XY:

AN XY:

36049

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:

31519

American (AMR)

AF:

0.00

AC:

AN:

10915

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2662

East Asian (EAS)

AF:

0.00

AC:

AN:

3610

South Asian (SAS)

AF:

0.00

AC:

AN:

2873

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6414

Middle Eastern (MID)

AF:

0.00

AC:

AN:

218

European-Non Finnish (NFE)

AF:

0.0000374

AC:

AN:

53466

Other (OTH)

AF:

0.00

AC:

AN:

1555

⚠️ 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.:

Bravo

AF:

0.0000378

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Adrenoleukodystrophy

Uncertain:2Benign:1

Nov 07, 2021

Genome-Nilou Lab

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 16, 2018

Mayo Clinic Laboratories, Mayo Clinic

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 24, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.50

BayesDel_addAF

Uncertain

0.054

BayesDel_noAF

Benign

-0.16

CADD

Benign

(source)

DANN

Benign

0.77

DEOGEN2

Pathogenic

0.87

D;D

FATHMM_MKL

Benign

0.19

LIST_S2

Benign

0.84

T;T

M_CAP

Uncertain

0.28

MetaRNN

Benign

0.31

T;T

MetaSVM

Benign

-0.46

MutationAssessor

Benign

1.4

L;.

PhyloP100

-0.18

PrimateAI

Pathogenic

0.85

PROVEAN

Benign

-1.8

N;N

REVEL

Uncertain

0.34

Sift

Benign

0.64

T;T

Sift4G

Benign

0.65

T;T

Polyphen

0.0090

B;.

Vest4

0.34

MutPred

0.51

Gain of MoRF binding (P = 0.2003);.;

MVP

0.94

MPC

0.66

ClinPred

0.037

GERP RS

3.6

PromoterAI

0.095

Neutral

(source)

Varity_R

0.24

gMVP

0.83

Mutation Taster

=72/28

polymorphism

(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

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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