rs1432758988

Positions:

chrX-153736454-C-T

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_ModerateBP6BS2

The NM_000033.4(ABCD1):c.1334C>T(p.Ala445Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000297 in 1,210,718 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 11 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000044 ( 0 hom., 2 hem., cov: 24)

Exomes 𝑓: 0.000028 ( 0 hom. 9 hem. )

Consequence

ABCD1
NM_000033.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:1

Conservation

PhyloP100: -0.236

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 links:

ABCD1 (HGNC:):

ABCD1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -7 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.075837314).

BP6

Variant X-153736454-C-T is Benign according to our data. Variant chrX-153736454-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 458630.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.

BS2

High Hemizygotes in GnomAd4 at 2 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ABCD1	NM_000033.4 linkuse as main transcript	c.1334C>T	p.Ala445Val	missense_variant	4/10	ENST00000218104.6	NP_000024.2	P33897
ABCD1	XM_047441916.1 linkuse as main transcript	c.1334C>T	p.Ala445Val	missense_variant	4/11		XP_047297872.1
ABCD1	XM_047441917.1 linkuse as main transcript	c.1334C>T	p.Ala445Val	missense_variant	4/8		XP_047297873.1
LOC124905226	XR_007068350.1 linkuse as main transcript	n.3897G>A		non_coding_transcript_exon_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
ABCD1	ENST00000218104.6 linkuse as main transcript	c.1334C>T	p.Ala445Val	missense_variant	4/10	1	NM_000033.4	ENSP00000218104.3	P33897
ABCD1	ENST00000443684.2 linkuse as main transcript	n.337C>T		non_coding_transcript_exon_variant	3/6	3
PLXNB3-AS1	ENST00000434284.1 linkuse as main transcript	n.581-495G>A		intron_variant		3

Frequencies

GnomAD3 genomes

AF:

0.0000444

AC:

AN:

112579

Hom.:

Cov.:

AF XY:

0.0000576

AC XY:

AN XY:

34751

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:

0.000362

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000752

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000164

AC:

AN:

182753

Hom.:

AF XY:

0.0000148

AC XY:

AN XY:

67633

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 SAS exome

AF:

0.0000524

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000246

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000282

AC:

AN:

1098139

Hom.:

Cov.:

AF XY:

0.0000248

AC XY:

AN XY:

363527

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000923

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000297

Gnomad4 OTH exome

AF:

0.0000217

GnomAD4 genome

AF:

0.0000444

AC:

AN:

112579

Hom.:

Cov.:

AF XY:

0.0000576

AC XY:

AN XY:

34751

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000362

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000752

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000227

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:3

Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Uncertain significance, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Uncertain significance, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 20, 2024

The c.1334C>T (p.A445V) alteration is located in exon 4 (coding exon 4) of the ABCD1 gene. This alteration results from a C to T substitution at nucleotide position 1334, causing the alanine (A) at amino acid position 445 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Adrenoleukodystrophy

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 19, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.073

BayesDel_addAF

Benign

-0.15

BayesDel_noAF

Benign

-0.30

CADD

Benign

4.3

DANN

Benign

0.91

DEOGEN2

Benign

0.41

FATHMM_MKL

Benign

0.057

LIST_S2

Benign

0.44

M_CAP

Benign

0.075

MetaRNN

Benign

0.076

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.56

PrimateAI

Benign

0.27

PROVEAN

Benign

-0.82

REVEL

Benign

0.17

Sift

Benign

0.46

Sift4G

Benign

0.53

Polyphen

0.0030

Vest4

0.13

MutPred

0.29

Loss of helix (P = 0.0558);

MVP

0.79

MPC

0.56

ClinPred

0.023

GERP RS

1.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.032

gMVP

0.61

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.15

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over