rs376472029

Positions:

chrX-153740185-G-A

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4BS2

The NM_000033.4(ABCD1):c.1582G>A(p.Gly528Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000033 in 1,210,480 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 15 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/20 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 0.000089 ( 0 hom., 4 hem., cov: 24)

Exomes 𝑓: 0.000027 ( 0 hom. 11 hem. )

Consequence

ABCD1
NM_000033.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:1

Conservation

PhyloP100: 1.89

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 Likely_benign. Variant got -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.3270386).

BS2

High Hemizygotes in GnomAd4 at 4 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ABCD1	NM_000033.4 linkuse as main transcript	c.1582G>A	p.Gly528Ser	missense_variant	6/10	ENST00000218104.6	NP_000024.2	P33897
ABCD1	XM_047441916.1 linkuse as main transcript	c.1882G>A	p.Gly628Ser	missense_variant	7/11		XP_047297872.1
ABCD1	XM_047441917.1 linkuse as main transcript	c.1638G>A	p.Thr546Thr	synonymous_variant	7/8		XP_047297873.1
LOC124905226	XR_007068350.1 linkuse as main transcript	n.1363C>T		non_coding_transcript_exon_variant	1/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
ABCD1	ENST00000218104.6 linkuse as main transcript	c.1582G>A	p.Gly528Ser	missense_variant	6/10	1	NM_000033.4	ENSP00000218104.3	P33897
ABCD1	ENST00000443684.2 linkuse as main transcript	n.585G>A		non_coding_transcript_exon_variant	5/6	3
PLXNB3-AS1	ENST00000434284.1 linkuse as main transcript	n.72-1607C>T		intron_variant		3

Frequencies

GnomAD3 genomes

AF:

0.0000887

AC:

AN:

112790

Hom.:

Cov.:

AF XY:

0.000114

AC XY:

AN XY:

34942

show subpopulations

Gnomad AFR

AF:

0.000161

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000930

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:

0.0000751

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000328

AC:

AN:

182731

Hom.:

AF XY:

0.00

AC XY:

AN XY:

67241

show subpopulations

Gnomad AFR exome

AF:

0.000152

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000490

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000273

AC:

AN:

1097690

Hom.:

Cov.:

AF XY:

0.0000303

AC XY:

AN XY:

363090

show subpopulations

Gnomad4 AFR exome

AF:

0.0000379

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000495

Gnomad4 NFE exome

AF:

0.0000309

Gnomad4 OTH exome

AF:

0.0000217

GnomAD4 genome

AF:

0.0000887

AC:

AN:

112790

Hom.:

Cov.:

AF XY:

0.000114

AC XY:

AN XY:

34942

show subpopulations

Gnomad4 AFR

AF:

0.000161

Gnomad4 AMR

AF:

0.0000930

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000751

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000270

Hom.:

Bravo

AF:

0.000106

ESP6500AA

AF:

0.000261

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000330

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Adrenoleukodystrophy

Uncertain:2Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 31, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 22, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 07, 2021	- -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Mar 16, 2018

The G528S variant in the ABCD1 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The G528S variant was not observed at any significant frequency in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The G528S variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is not conserved. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. We interpret G528S as a variant of uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.074

BayesDel_addAF

Benign

-0.10

BayesDel_noAF

Benign

-0.13

CADD

Benign

6.2

DANN

Benign

0.93

DEOGEN2

Uncertain

0.73

FATHMM_MKL

Benign

0.12

LIST_S2

Benign

0.79

M_CAP

Uncertain

0.19

MetaRNN

Benign

0.33

MetaSVM

Uncertain

-0.13

MutationAssessor

Benign

-0.040

PrimateAI

Benign

0.32

PROVEAN

Benign

-1.0

REVEL

Uncertain

0.38

Sift

Benign

0.098

Sift4G

Benign

0.25

Polyphen

0.0060

Vest4

0.20

MVP

0.89

MPC

0.58

ClinPred

0.023

GERP RS

3.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.13

gMVP

0.77

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

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