rs45568335

Positions:

chr14-74290035-G-A

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 1P and 9B. PP3BP6BS1BS2

The NM_005050.4(ABCD4):c.1411C>T(p.Arg471Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00191 in 1,614,138 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0016 ( 1 hom., cov: 31)

Exomes 𝑓: 0.0019 ( 10 hom. )

Consequence

ABCD4
NM_005050.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:5

Conservation

PhyloP100: 3.03

Variant links:

Genes affected

ABCD4 (HGNC:68): (ATP binding cassette subfamily D member 4) 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. The function of this peroxisomal membrane protein is unknown. However, it is speculated that it may function as a heterodimer for another peroxisomal ABC transporter and, therefore, may modify the adrenoleukodystrophy phenotype. It may also play a role in the process of peroxisome biogenesis. Alternative splicing results in several protein-coding and non-protein-coding variants. [provided by RefSeq, Jul 2017]

ABCD4 links:

ENSG00000258559 (HGNC:):

ENSG00000258559 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

PP3

Multiple lines of computational evidence support a deleterious effect 8: AlphaMissense, BayesDel_noAF, Cadd, Dann, Eigen, PrimateAI, PROVEAN, REVEL [when FATHMM_MKL, MetaRNN, MutationTaster, phyloP100way_vertebrate was below the threshold]

BP6

Variant 14-74290035-G-A is Benign according to our data. Variant chr14-74290035-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 381876.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Likely_benign=4}. Variant chr14-74290035-G-A is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00164 (249/152254) while in subpopulation AMR AF= 0.00262 (40/15296). AF 95% confidence interval is 0.00199. There are 1 homozygotes in gnomad4. There are 130 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 10 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ABCD4	NM_005050.4 link	c.1411C>T	p.Arg471Trp	missense_variant	13/19	ENST00000356924.9	NP_005041.1	O14678A0A024R6B9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ABCD4	ENST00000356924.9 link	c.1411C>T	p.Arg471Trp	missense_variant	13/19	1	NM_005050.4	ENSP00000349396.4		O14678

Frequencies

GnomAD3 genomes

AF:

0.00164

AC:

249

AN:

152136

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000652

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00262

Gnomad ASJ

AF:

0.00259

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00104

Gnomad FIN

AF:

0.000659

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00228

Gnomad OTH

AF:

0.00287

GnomAD3 exomes

AF:

0.00155

AC:

390

AN:

251442

Hom.:

AF XY:

0.00158

AC XY:

215

AN XY:

135902

show subpopulations

Gnomad AFR exome

AF:

0.000554

Gnomad AMR exome

AF:

0.00142

Gnomad ASJ exome

AF:

0.00208

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000980

Gnomad FIN exome

AF:

0.000508

Gnomad NFE exome

AF:

0.00222

Gnomad OTH exome

AF:

0.00293

GnomAD4 exome

AF:

0.00194

AC:

2838

AN:

1461884

Hom.:

Cov.:

AF XY:

0.00188

AC XY:

1368

AN XY:

727244

show subpopulations

Gnomad4 AFR exome

AF:

0.000568

Gnomad4 AMR exome

AF:

0.00159

Gnomad4 ASJ exome

AF:

0.00241

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000800

Gnomad4 FIN exome

AF:

0.000768

Gnomad4 NFE exome

AF:

0.00219

Gnomad4 OTH exome

AF:

0.00169

GnomAD4 genome

AF:

0.00164

AC:

249

AN:

152254

Hom.:

Cov.:

AF XY:

0.00175

AC XY:

130

AN XY:

74446

show subpopulations

Gnomad4 AFR

AF:

0.000650

Gnomad4 AMR

AF:

0.00262

Gnomad4 ASJ

AF:

0.00259

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00104

Gnomad4 FIN

AF:

0.000659

Gnomad4 NFE

AF:

0.00228

Gnomad4 OTH

AF:

0.00284

Alfa

AF:

0.00184

Hom.:

Bravo

AF:

0.00171

TwinsUK

AF:

0.00189

AC:

ALSPAC

AF:

0.00259

AC:

ESP6500AA

AF:

0.000681

AC:

ESP6500EA

AF:

0.00140

AC:

ExAC

AF:

0.00168

AC:

204

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00240

EpiControl

AF:

0.00196

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Methylmalonic acidemia with homocystinuria, type cblJ

Uncertain:1Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
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	Jan 30, 2024	- -

not provided

Uncertain:1Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2023	ABCD4: PP3, BS2 -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jan 06, 2023	BS1, PP3 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 29, 2020	Has not been previously published as pathogenic or benign to our knowledge; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 20849526) -

ABCD4-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 09, 2024

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.65

BayesDel_addAF

Uncertain

0.14

BayesDel_noAF

Pathogenic

0.43

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.62

Eigen

Pathogenic

0.74

Eigen_PC

Pathogenic

0.71

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.94

M_CAP

Uncertain

0.19

MetaRNN

Benign

0.20

MetaSVM

Pathogenic

1.0

MutationAssessor

Uncertain

2.8

PrimateAI

Pathogenic

0.84

PROVEAN

Pathogenic

-5.5

REVEL

Pathogenic

0.89

Sift

Uncertain

0.0020

Sift4G

Uncertain

0.0020

Polyphen

1.0

Vest4

0.96

MVP

0.99

MPC

0.90

ClinPred

0.040

GERP RS

5.8

Varity_R

0.72

gMVP

0.93

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.24

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.24

Position offset: -8

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