rs782161942

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The ENST00000218104.6(ABCD1):c.41C>G(p.Thr14Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000619 in 1,148,054 control chromosomes in the GnomAD database, including 1 homozygotes. There are 200 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T14A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00044 ( 1 hom., 7 hem., cov: 25)

Exomes 𝑓: 0.00064 ( 0 hom. 193 hem. )

Consequence

ABCD1
ENST00000218104.6 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:8

Conservation

PhyloP100: 0.462

Publications

1 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: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.019428253).

BP6

Variant X-153725307-C-G is Benign according to our data. Variant chrX-153725307-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 458643.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000442 (50/113096) while in subpopulation AMR AF = 0.000642 (7/10896). AF 95% confidence interval is 0.000453. There are 1 homozygotes in GnomAd4. There are 7 alleles in the male GnomAd4 subpopulation. Median coverage is 25. This position passed quality control check.

BS2

High AC in GnomAd4 at 50 XL,AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000218104.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ABCD1	NM_000033.4	MANE Select	c.41C>G	p.Thr14Arg	missense	Exon 1 of 10	NP_000024.2
	ABCD1	NM_001440747.1		c.41C>G	p.Thr14Arg	missense	Exon 1 of 11	NP_001427676.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ABCD1	ENST00000218104.6	TSL:1 MANE Select	c.41C>G	p.Thr14Arg	missense	Exon 1 of 10	ENSP00000218104.3

Frequencies

GnomAD3 genomes

AF:

0.000442

AC:

AN:

113096

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000961

Gnomad AMI

AF:

0.0103

Gnomad AMR

AF:

0.000642

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:

0.000620

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000394

AC:

AN:

86391

AF XY:

0.000282

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000116

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000149

Gnomad NFE exome

AF:

0.000974

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000639

AC:

661

AN:

1034958

Hom.:

Cov.:

AF XY:

0.000579

AC XY:

193

AN XY:

333206

show subpopulations

African (AFR)

AF:

0.0000412

AC:

AN:

24247

American (AMR)

AF:

0.000151

AC:

AN:

26478

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

18023

East Asian (EAS)

AF:

0.00

AC:

AN:

26739

South Asian (SAS)

AF:

0.00

AC:

AN:

48408

European-Finnish (FIN)

AF:

0.000316

AC:

AN:

31600

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3018

European-Non Finnish (NFE)

AF:

0.000768

AC:

624

AN:

812799

Other (OTH)

AF:

0.000504

AC:

AN:

43646

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.491

Heterozygous variant carriers

121

151

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

104

130

<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:

0.000442

AC:

AN:

113096

Hom.:

Cov.:

AF XY:

0.000199

AC XY:

AN XY:

35242

show subpopulations

African (AFR)

AF:

0.0000961

AC:

AN:

31203

American (AMR)

AF:

0.000642

AC:

AN:

10896

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2651

East Asian (EAS)

AF:

0.00

AC:

AN:

3560

South Asian (SAS)

AF:

0.00

AC:

AN:

2835

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6298

Middle Eastern (MID)

AF:

0.00

AC:

AN:

239

European-Non Finnish (NFE)

AF:

0.000620

AC:

AN:

53211

Other (OTH)

AF:

0.00

AC:

AN:

1526

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.470

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

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:

0.000437

Hom.:

Bravo

AF:

0.000487

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.00138

AC:

ExAC

AF:

0.0000653

AC:

ClinVar

ClinVar submissions as Germline

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Adrenoleukodystrophy (5)

not provided (4)

ABCD1-related disorder (1)

Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.086

BayesDel_addAF

Benign

-0.28

BayesDel_noAF

Benign

-0.24

CADD

Benign

(source)

DANN

Benign

0.96

DEOGEN2

Uncertain

0.43

FATHMM_MKL

Uncertain

0.88

LIST_S2

Benign

0.72

M_CAP

Pathogenic

0.35

MetaRNN

Benign

0.019

MetaSVM

Benign

-0.45

MutationAssessor

Benign

0.55

PhyloP100

0.46

PrimateAI

Uncertain

0.63

PROVEAN

Benign

-0.57

REVEL

Benign

0.21

Sift

Benign

0.17

Sift4G

Benign

0.49

Polyphen

0.24

Vest4

0.073

MutPred

0.40

Gain of solvent accessibility (P = 0.0055)

MVP

0.87

MPC

0.65

ClinPred

0.025

GERP RS

2.2

PromoterAI

0.042

Neutral

(source)

Varity_R

0.14

gMVP

0.69

Mutation Taster

=98/2

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over