14-74286438-C-T

Variant names:

• chr14-74286438-C-T
• rs1052006
• NM_005050.4:c.*23G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Moderate BP6_Moderate BA1

The NM_005050.4(ABCD4):​c.*23G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00774 in 1,613,570 control chromosomes in the GnomAD database, including 879 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.042 (492 hom., cov: 33)
  • Exomes 𝑓: 0.0042 (387 hom.)
• Consequence: ABCD4 NM_005050.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.808
• Publications: 2 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: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics, Orphanet, ClinGen

ACMG classification

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

• BP4: Computational evidence support a benign effect (REVEL=0.051).
• BP6: Variant 14-74286438-C-T is Benign according to our data. Variant chr14-74286438-C-T is described in ClinVar as Benign. ClinVar VariationId is 1292530.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.143 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ABCD4	NM_005050.4	MANE Select	c.*23G>A		3_prime_UTR	Exon 19 of 19	NP_005041.1	O14678
	ABCD4	NM_020325.3		c.*236G>A		3_prime_UTR	Exon 18 of 18	NP_064730.1
	ABCD4	NM_001440752.1		c.*352G>A		3_prime_UTR	Exon 18 of 18	NP_001427681.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ABCD4	ENST00000356924.9	TSL:1 MANE Select	c.*23G>A		3_prime_UTR	Exon 19 of 19	ENSP00000349396.4	O14678
	ABCD4	ENST00000553486.5	TSL:1	n.*1545G>A		non_coding_transcript_exon	Exon 18 of 18	ENSP00000450611.1	E9PI46
	ABCD4	ENST00000553486.5	TSL:1	n.*1545G>A		3_prime_UTR	Exon 18 of 18	ENSP00000450611.1	E9PI46

Frequencies

GnomAD3 genomes AF: 0.0417 AC: 6348 AN: 152202 Hom.: 492 Cov.: 33

Gnomad AFR AF: 0.146

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0146

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000353

Gnomad OTH AF: 0.0301

GnomAD2 exomes AF: 0.0106 AC: 2674 AN: 251210 AF XY: 0.00769

Gnomad AFR exome AF: 0.148

Gnomad AMR exome AF: 0.00616

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000211

Gnomad OTH exome AF: 0.00425

GnomAD4 exome AF: 0.00419 AC: 6126 AN: 1461250 Hom.: 387 Cov.: 29 AF XY: 0.00360 AC XY: 2617 AN XY: 726990

African (AFR) AF: 0.150 AC: 5031 AN: 33468

American (AMR) AF: 0.00698 AC: 312 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.000220 AC: 19 AN: 86250

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53292

Middle Eastern (MID) AF: 0.00555 AC: 32 AN: 5766

European-Non Finnish (NFE) AF: 0.000152 AC: 169 AN: 1111542

Other (OTH) AF: 0.00931 AC: 562 AN: 60380

GnomAD4 genome AF: 0.0417 AC: 6359 AN: 152320 Hom.: 492 Cov.: 33 AF XY: 0.0393 AC XY: 2927 AN XY: 74488

African (AFR) AF: 0.146 AC: 6048 AN: 41544

American (AMR) AF: 0.0146 AC: 223 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000353 AC: 24 AN: 68036

Other (OTH) AF: 0.0298 AC: 63 AN: 2116

Alfa AF: 0.0147 Hom.: 180

Bravo AF: 0.0474

Asia WGS AF: 0.0110 AC: 38 AN: 3478

EpiCase AF: 0.000327

EpiControl AF: 0.000178

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	6.3
DANN	Benign	0.76
PhyloP100		0.81
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: rs1052006; hg19: chr14-74753141;