chr14-74300808-G-A

Variant names:

• chr14-74300808-G-A
• rs17182959
• NM_005050.4:c.39-540C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_005050.4(ABCD4):​c.39-540C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.615 in 151,980 control chromosomes in the GnomAD database, including 30,656 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.61 (30656 hom., cov: 31)
• Consequence: ABCD4 NM_005050.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.131
• Publications: 6 publications found

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 Gene-Disease associations (from GenCC):

• methylmalonic acidemia with homocystinuria, type cblJ

  Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), G2P, Orphanet, Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.99).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.828 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ABCD4	NM_005050.4	c.39-540C>T		intron_variant	Intron 1 of 18	ENST00000356924.9	NP_005041.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ABCD4	ENST00000356924.9	c.39-540C>T		intron_variant	Intron 1 of 18	1	NM_005050.4	ENSP00000349396.4

Frequencies

GnomAD3 genomes AF: 0.615 AC: 93359 AN: 151862 Hom.: 30611 Cov.: 31

Gnomad AFR AF: 0.835

Gnomad AMI AF: 0.501

Gnomad AMR AF: 0.577

Gnomad ASJ AF: 0.656

Gnomad EAS AF: 0.830

Gnomad SAS AF: 0.585

Gnomad FIN AF: 0.397

Gnomad MID AF: 0.774

Gnomad NFE AF: 0.506

Gnomad OTH AF: 0.651

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.615 AC: 93458 AN: 151980 Hom.: 30656 Cov.: 31 AF XY: 0.609 AC XY: 45216 AN XY: 74250

African (AFR) AF: 0.835 AC: 34649 AN: 41476

American (AMR) AF: 0.576 AC: 8802 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.656 AC: 2271 AN: 3464

East Asian (EAS) AF: 0.831 AC: 4291 AN: 5166

South Asian (SAS) AF: 0.585 AC: 2815 AN: 4810

European-Finnish (FIN) AF: 0.397 AC: 4181 AN: 10530

Middle Eastern (MID) AF: 0.777 AC: 227 AN: 292

European-Non Finnish (NFE) AF: 0.506 AC: 34390 AN: 67950

Other (OTH) AF: 0.652 AC: 1375 AN: 2110

Alfa AF: 0.558 Hom.: 30056

Bravo AF: 0.639

Asia WGS AF: 0.704 AC: 2446 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.99
CADD	Benign	2.9
DANN	Benign	0.52
PhyloP100		0.13
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs17182959; hg19: chr14-74767511;