rs150151955

Positions:

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 2P and 16B. PM1BP4_StrongBP6_Very_StrongBS2

The ENST00000218104.6(ABCD1):c.757C>G(p.Leu253Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00119 in 1,204,688 control chromosomes in the GnomAD database, including 1 homozygotes. There are 461 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L253F) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00061 ( 0 hom., 18 hem., cov: 26)

Exomes 𝑓: 0.0013 ( 1 hom. 443 hem. )

Consequence

ABCD1
ENST00000218104.6 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13

Conservation

PhyloP100: 1.23

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -14 ACMG points.

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 8 uncertain in ENST00000218104.6

BP4

Computational evidence support a benign effect (MetaRNN=0.044420302).

BP6

Variant X-153726023-C-G is Benign according to our data. Variant chrX-153726023-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 377034.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-153726023-C-G is described in Lovd as [Likely_benign].

BS2

High Hemizygotes in GnomAd4 at 18 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
ABCD1	NM_000033.4 linkuse as main transcript	c.757C>G	p.Leu253Val	missense_variant	1/10	ENST00000218104.6	NP_000024.2
ABCD1	XM_047441916.1 linkuse as main transcript	c.757C>G	p.Leu253Val	missense_variant	1/11		XP_047297872.1
ABCD1	XM_047441917.1 linkuse as main transcript	c.757C>G	p.Leu253Val	missense_variant	1/8		XP_047297873.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ABCD1	ENST00000218104.6 linkuse as main transcript	c.757C>G	p.Leu253Val	missense_variant	1/10	1	NM_000033.4	ENSP00000218104	P1
ABCD1	ENST00000370129.4 linkuse as main transcript	c.202C>G	p.Leu68Val	missense_variant	1/2	2		ENSP00000359147

Frequencies

GnomAD3 genomes

AF:

0.000614

AC:

AN:

113921

Hom.:

Cov.:

AF XY:

0.000499

AC XY:

AN XY:

36041

show subpopulations

Gnomad AFR

AF:

0.000254

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000183

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000347

Gnomad FIN

AF:

0.000622

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00103

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000829

AC:

143

AN:

172513

Hom.:

AF XY:

0.000598

AC XY:

AN XY:

60237

show subpopulations

Gnomad AFR exome

AF:

0.000241

Gnomad AMR exome

AF:

0.0000750

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000111

Gnomad FIN exome

AF:

0.00126

Gnomad NFE exome

AF:

0.00145

Gnomad OTH exome

AF:

0.00164

GnomAD4 exome

AF:

0.00126

AC:

1369

AN:

1090714

Hom.:

Cov.:

AF XY:

0.00124

AC XY:

443

AN XY:

357750

show subpopulations

Gnomad4 AFR exome

AF:

0.000267

Gnomad4 AMR exome

AF:

0.0000287

Gnomad4 ASJ exome

AF:

0.0000526

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000561

Gnomad4 FIN exome

AF:

0.00117

Gnomad4 NFE exome

AF:

0.00150

Gnomad4 OTH exome

AF:

0.00127

GnomAD4 genome

AF:

0.000614

AC:

AN:

113974

Hom.:

Cov.:

AF XY:

0.000499

AC XY:

AN XY:

36104

show subpopulations

Gnomad4 AFR

AF:

0.000254

Gnomad4 AMR

AF:

0.000183

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000348

Gnomad4 FIN

AF:

0.000622

Gnomad4 NFE

AF:

0.00103

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.00118

Hom.:

Bravo

AF:

0.000680

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.00173

AC:

ESP6500AA

AF:

0.000262

AC:

ESP6500EA

AF:

0.00149

AC:

ExAC

AF:

0.00112

AC:

136

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:7

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 12, 2018	In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 30487145, 33151932) -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2024	ABCD1: BS1, BS2 -
Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Oct 27, 2016	- -

Adrenoleukodystrophy

Benign:4

Likely benign, no assertion criteria provided	clinical testing	Natera, Inc.	Feb 25, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 25, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 07, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Apr 08, 2019

- -

Inborn genetic diseases

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 12, 2017

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.076

BayesDel_addAF

Benign

-0.020

BayesDel_noAF

Pathogenic

0.18

CADD

Benign

DANN

Benign

0.97

DEOGEN2

Uncertain

0.77

D;D

FATHMM_MKL

Benign

0.48

LIST_S2

Benign

0.79

T;T

M_CAP

Pathogenic

0.38

MetaRNN

Benign

0.044

T;T

MetaSVM

Uncertain

0.15

MutationAssessor

Benign

0.53

N;.

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.75

PROVEAN

Benign

-0.97

N;N

REVEL

Uncertain

0.61

Sift

Benign

0.19

T;T

Sift4G

Benign

0.15

T;T

Polyphen

0.37

B;.

Vest4

0.33

MVP

1.0

MPC

0.63

ClinPred

0.014

GERP RS

5.4

Varity_R

0.26

gMVP

0.83

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