rs147795328

Positions:

chr14-74292363-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_005050.4(ABCD4):c.1042C>T(p.Arg348Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00138 in 1,614,070 control chromosomes in the GnomAD database, including 37 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.00092 ( 2 hom., cov: 32)

Exomes 𝑓: 0.0014 ( 35 hom. )

Consequence

ABCD4
NM_005050.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 3.09

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0085271895).

BP6

Variant 14-74292363-G-A is Benign according to our data. Variant chr14-74292363-G-A is described in ClinVar as [Benign]. Clinvar id is 389017.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-74292363-G-A is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000919 (140/152296) while in subpopulation SAS AF= 0.016 (77/4818). AF 95% confidence interval is 0.0131. There are 2 homozygotes in gnomad4. There are 94 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ABCD4	NM_005050.4 link	c.1042C>T	p.Arg348Trp	missense_variant	11/19	ENST00000356924.9	NP_005041.1	O14678A0A024R6B9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ABCD4	ENST00000356924.9 link	c.1042C>T	p.Arg348Trp	missense_variant	11/19	1	NM_005050.4	ENSP00000349396.4		O14678

Frequencies

GnomAD3 genomes

AF:

0.000927

AC:

141

AN:

152178

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000507

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000589

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000385

Gnomad SAS

AF:

0.0162

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000412

Gnomad OTH

AF:

0.00144

GnomAD3 exomes

AF:

0.00256

AC:

644

AN:

251188

Hom.:

AF XY:

0.00348

AC XY:

472

AN XY:

135756

show subpopulations

Gnomad AFR exome

AF:

0.000554

Gnomad AMR exome

AF:

0.000347

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0180

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000590

Gnomad OTH exome

AF:

0.000653

GnomAD4 exome

AF:

0.00143

AC:

2094

AN:

1461774

Hom.:

Cov.:

AF XY:

0.00196

AC XY:

1425

AN XY:

727188

show subpopulations

Gnomad4 AFR exome

AF:

0.000478

Gnomad4 AMR exome

AF:

0.000380

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0175

Gnomad4 FIN exome

AF:

0.0000563

Gnomad4 NFE exome

AF:

0.000363

Gnomad4 OTH exome

AF:

0.00179

GnomAD4 genome

AF:

0.000919

AC:

140

AN:

152296

Hom.:

Cov.:

AF XY:

0.00126

AC XY:

AN XY:

74456

show subpopulations

Gnomad4 AFR

AF:

0.000505

Gnomad4 AMR

AF:

0.000588

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000386

Gnomad4 SAS

AF:

0.0160

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000412

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.000538

Hom.:

Bravo

AF:

0.000582

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.00268

AC:

326

Asia WGS

AF:

0.00433

AC:

AN:

3478

EpiCase

AF:

0.000981

EpiControl

AF:

0.000711

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Methylmalonic acidemia with homocystinuria, type cblJ

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 18, 2024

- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Oct 11, 2016

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

not provided

Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

ABCD4-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 26, 2019

This variant is classified as 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

Benign

0.15

BayesDel_addAF

Benign

-0.21

BayesDel_noAF

Uncertain

-0.060

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.058

Eigen

Benign

-0.046

Eigen_PC

Benign

0.050

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.85

MetaRNN

Benign

0.0085

MetaSVM

Uncertain

0.15

MutationAssessor

Benign

1.1

PrimateAI

Benign

0.23

PROVEAN

Benign

-0.68

REVEL

Uncertain

0.41

Sift

Benign

0.19

Sift4G

Uncertain

0.025

Polyphen

0.012

Vest4

0.32

MVP

1.0

MPC

0.25

ClinPred

0.010

GERP RS

4.2

Varity_R

0.12

gMVP

0.76

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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