14-74300425-G-A

Variant names:

• chr14-74300425-G-A
• rs7158118
• NM_005050.4:c.39-157C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_005050.4(ABCD4):​c.39-157C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.576 in 151,550 control chromosomes in the GnomAD database, including 26,273 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency: Genomes: 𝑓 0.58 (26273 hom., cov: 29)
• Consequence: ABCD4 NM_005050.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.0820
• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 14-74300425-G-A is Benign according to our data. Variant chr14-74300425-G-A is described in ClinVar as Benign. ClinVar VariationId is 1259229.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.809 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005050.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ABCD4	NM_005050.4	MANE Select	c.39-157C>T		intron	N/A	NP_005041.1
	ABCD4	NM_020325.3		c.39-157C>T		intron	N/A	NP_064730.1
	ABCD4	NM_001440752.1		c.39-157C>T		intron	N/A	NP_001427681.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ABCD4	ENST00000356924.9	TSL:1 MANE Select	c.39-157C>T		intron	N/A	ENSP00000349396.4
	ABCD4	ENST00000460308.6	TSL:1	n.39-157C>T		intron	N/A	ENSP00000436527.2
	ABCD4	ENST00000469672.5	TSL:1	n.39-750C>T		intron	N/A	ENSP00000434626.1

Frequencies

GnomAD3 genomes AF: 0.576 AC: 87174 AN: 151434 Hom.: 26237 Cov.: 29

Gnomad AFR AF: 0.724

Gnomad AMI AF: 0.501

Gnomad AMR AF: 0.556

Gnomad ASJ AF: 0.628

Gnomad EAS AF: 0.829

Gnomad SAS AF: 0.579

Gnomad FIN AF: 0.394

Gnomad MID AF: 0.766

Gnomad NFE AF: 0.494

Gnomad OTH AF: 0.623

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

GnomAD4 genome AF: 0.576 AC: 87267 AN: 151550 Hom.: 26273 Cov.: 29 AF XY: 0.572 AC XY: 42307 AN XY: 73996

African (AFR) AF: 0.725 AC: 29943 AN: 41318

American (AMR) AF: 0.556 AC: 8460 AN: 15210

Ashkenazi Jewish (ASJ) AF: 0.628 AC: 2177 AN: 3464

East Asian (EAS) AF: 0.829 AC: 4240 AN: 5112

South Asian (SAS) AF: 0.580 AC: 2777 AN: 4792

European-Finnish (FIN) AF: 0.394 AC: 4136 AN: 10492

Middle Eastern (MID) AF: 0.769 AC: 226 AN: 294

European-Non Finnish (NFE) AF: 0.494 AC: 33539 AN: 67854

Other (OTH) AF: 0.624 AC: 1314 AN: 2106

Alfa AF: 0.529 Hom.: 42930

Bravo AF: 0.596

Asia WGS AF: 0.695 AC: 2413 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Jul 07, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	1.0
DANN	Benign	0.54
PhyloP100		-0.082
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: rs7158118; hg19: chr14-74767128;