14-74299649-A-G

Position:

• chr14-74299649-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001353593.2(ABCD4):​c.-78T>C variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.347 in 1,612,364 control chromosomes in the GnomAD database, including 100,730 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.30 (7521 hom., cov: 32)
  • Exomes 𝑓: 0.35 (93209 hom.)
• Consequence: ABCD4 NM_001353593.2 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.135

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.59).
• BP6: Variant 14-74299649-A-G is Benign according to our data. Variant chr14-74299649-A-G is described in ClinVar as [Benign]. Clinvar id is 259620.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-74299649-A-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.365 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ABCD4	NM_005050.4	c.184T>C	p.Leu62Leu	synonymous_variant	3/19	ENST00000356924.9	NP_005041.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ABCD4	ENST00000356924.9	c.184T>C	p.Leu62Leu	synonymous_variant	3/19	1	NM_005050.4	ENSP00000349396.4

Frequencies

GnomAD3 genomes AF: 0.302 AC: 45911 AN: 151998 Hom.: 7530 Cov.: 32

Gnomad AFR AF: 0.168

Gnomad AMI AF: 0.470

Gnomad AMR AF: 0.303

Gnomad ASJ AF: 0.443

Gnomad EAS AF: 0.253

Gnomad SAS AF: 0.361

Gnomad FIN AF: 0.311

Gnomad MID AF: 0.557

Gnomad NFE AF: 0.369

Gnomad OTH AF: 0.358

GnomAD3 exomes AF: 0.325 AC: 81073 AN: 249452 Hom.: 14209 AF XY: 0.338 AC XY: 45581 AN XY: 134746

Gnomad AFR exome AF: 0.161

Gnomad AMR exome AF: 0.223

Gnomad ASJ exome AF: 0.437

Gnomad EAS exome AF: 0.242

Gnomad SAS exome AF: 0.367

Gnomad FIN exome AF: 0.311

Gnomad NFE exome AF: 0.372

Gnomad OTH exome AF: 0.373

GnomAD4 exome AF: 0.352 AC: 514010 AN: 1460248 Hom.: 93209 Cov.: 34 AF XY: 0.355 AC XY: 258047 AN XY: 726364

Gnomad4 AFR exome AF: 0.161

Gnomad4 AMR exome AF: 0.230

Gnomad4 ASJ exome AF: 0.444

Gnomad4 EAS exome AF: 0.242

Gnomad4 SAS exome AF: 0.371

Gnomad4 FIN exome AF: 0.314

Gnomad4 NFE exome AF: 0.364

Gnomad4 OTH exome AF: 0.358

GnomAD4 genome AF: 0.302 AC: 45903 AN: 152116 Hom.: 7521 Cov.: 32 AF XY: 0.300 AC XY: 22290 AN XY: 74360

Gnomad4 AFR AF: 0.168

Gnomad4 AMR AF: 0.302

Gnomad4 ASJ AF: 0.443

Gnomad4 EAS AF: 0.253

Gnomad4 SAS AF: 0.359

Gnomad4 FIN AF: 0.311

Gnomad4 NFE AF: 0.369

Gnomad4 OTH AF: 0.359

Alfa AF: 0.353 Hom.: 14152

Bravo AF: 0.293

Asia WGS AF: 0.308 AC: 1069 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Methylmalonic acidemia with homocystinuria, type cblJ Benign:3

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 14, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 02, 2015	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

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- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.59
CADD	Benign	6.4
DANN	Benign	0.88

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

Other links and lift over

dbSNP: rs2301345; hg19: chr14-74766352; COSMIC: COSV53992812; COSMIC: COSV53992812;