14-74292356-G-C

Position:

chr14-74292356-G-C

Variant summary

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

The ENST00000356924.9(ABCD4):c.1049C>G(p.Thr350Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0241 in 1,614,040 control chromosomes in the GnomAD database, including 555 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T350M) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.019 ( 37 hom., cov: 33)

Exomes 𝑓: 0.025 ( 518 hom. )

Consequence

ABCD4
ENST00000356924.9 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 3.61

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:

(HGNC:):

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=0.006796807).

BP6

Variant 14-74292356-G-C is Benign according to our data. Variant chr14-74292356-G-C is described in ClinVar as [Benign]. Clinvar id is 380512.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0187 (2847/152310) while in subpopulation NFE AF= 0.0272 (1853/68046). AF 95% confidence interval is 0.0262. There are 37 homozygotes in gnomad4. There are 1358 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 37 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ABCD4	NM_005050.4 linkuse as main transcript	c.1049C>G	p.Thr350Arg	missense_variant	11/19	ENST00000356924.9	NP_005041.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ABCD4	ENST00000356924.9 linkuse as main transcript	c.1049C>G	p.Thr350Arg	missense_variant	11/19	1	NM_005050.4	ENSP00000349396	P1
	ENST00000554532.2 linkuse as main transcript	n.1115+955C>G		intron_variant, non_coding_transcript_variant		4

Frequencies

GnomAD3 genomes

AF:

0.0187

AC:

2848

AN:

152192

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00613

Gnomad AMI

AF:

0.0307

Gnomad AMR

AF:

0.0271

Gnomad ASJ

AF:

0.0202

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00124

Gnomad FIN

AF:

0.0171

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0272

Gnomad OTH

AF:

0.0192

GnomAD3 exomes

AF:

0.0180

AC:

4514

AN:

251224

Hom.:

AF XY:

0.0175

AC XY:

2378

AN XY:

135778

show subpopulations

Gnomad AFR exome

AF:

0.00511

Gnomad AMR exome

AF:

0.0171

Gnomad ASJ exome

AF:

0.0244

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000555

Gnomad FIN exome

AF:

0.0165

Gnomad NFE exome

AF:

0.0272

Gnomad OTH exome

AF:

0.0214

GnomAD4 exome

AF:

0.0247

AC:

36069

AN:

1461730

Hom.:

518

Cov.:

AF XY:

0.0239

AC XY:

17394

AN XY:

727158

show subpopulations

Gnomad4 AFR exome

AF:

0.00358

Gnomad4 AMR exome

AF:

0.0173

Gnomad4 ASJ exome

AF:

0.0222

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000591

Gnomad4 FIN exome

AF:

0.0159

Gnomad4 NFE exome

AF:

0.0290

Gnomad4 OTH exome

AF:

0.0232

GnomAD4 genome

AF:

0.0187

AC:

2847

AN:

152310

Hom.:

Cov.:

AF XY:

0.0182

AC XY:

1358

AN XY:

74462

show subpopulations

Gnomad4 AFR

AF:

0.00611

Gnomad4 AMR

AF:

0.0270

Gnomad4 ASJ

AF:

0.0202

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00124

Gnomad4 FIN

AF:

0.0171

Gnomad4 NFE

AF:

0.0272

Gnomad4 OTH

AF:

0.0190

Alfa

AF:

0.0227

Hom.:

Bravo

AF:

0.0190

ESP6500AA

AF:

0.00658

AC:

ESP6500EA

AF:

0.0263

AC:

226

ExAC

AF:

0.0175

AC:

2124

Asia WGS

AF:

0.00115

AC:

AN:

3478

EpiCase

AF:

0.0298

EpiControl

AF:

0.0287

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:2

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 16, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jan 21, 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

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.19

BayesDel_addAF

Benign

-0.20

BayesDel_noAF

Uncertain

-0.050

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.062

Eigen

Benign

0.11

Eigen_PC

Uncertain

0.26

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.85

MetaRNN

Benign

0.0068

MetaSVM

Uncertain

0.19

MutationAssessor

Benign

2.0

MutationTaster

Benign

0.65

N;N

PrimateAI

Benign

0.35

PROVEAN

Benign

-1.1

REVEL

Uncertain

0.34

Sift

Benign

0.18

Sift4G

Benign

0.33

Polyphen

0.10

Vest4

0.097

MPC

0.29

ClinPred

0.011

GERP RS

5.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.26

gMVP

0.86

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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