14-74286404-C-G

Variant names:

• chr14-74286404-C-G
• rs1052012
• NM_005050.4:c.*57G>C

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.*57G>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0109 in 1,588,708 control chromosomes in the GnomAD database, including 1,612 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.057 (869 hom., cov: 33)
  • Exomes 𝑓: 0.0060 (743 hom.)
• Consequence: ABCD4 NM_005050.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.282
• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.01).
• BP6: Variant 14-74286404-C-G is Benign according to our data. Variant chr14-74286404-C-G is described in ClinVar as Benign. ClinVar VariationId is 1292531.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.196 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.*57G>C		3_prime_UTR	Exon 19 of 19	NP_005041.1	O14678
	ABCD4	NM_020325.3		c.*270G>C		3_prime_UTR	Exon 18 of 18	NP_064730.1
	ABCD4	NM_001440752.1		c.*386G>C		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.*57G>C		3_prime_UTR	Exon 19 of 19	ENSP00000349396.4	O14678
	ABCD4	ENST00000553486.5	TSL:1	n.*1579G>C		non_coding_transcript_exon	Exon 18 of 18	ENSP00000450611.1	E9PI46
	ABCD4	ENST00000553486.5	TSL:1	n.*1579G>C		3_prime_UTR	Exon 18 of 18	ENSP00000450611.1	E9PI46

Frequencies

GnomAD3 genomes AF: 0.0573 AC: 8712 AN: 152154 Hom.: 867 Cov.: 33

Gnomad AFR AF: 0.200

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0209

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.000676

Gnomad OTH AF: 0.0387

GnomAD2 exomes AF: 0.0148 AC: 3682 AN: 248922 AF XY: 0.0110

Gnomad AFR exome AF: 0.204

Gnomad AMR exome AF: 0.00875

Gnomad ASJ exome AF: 0.000100

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000506

Gnomad OTH exome AF: 0.00643

GnomAD4 exome AF: 0.00597 AC: 8573 AN: 1436436 Hom.: 743 Cov.: 25 AF XY: 0.00515 AC XY: 3686 AN XY: 716022

African (AFR) AF: 0.208 AC: 6848 AN: 32886

American (AMR) AF: 0.0104 AC: 462 AN: 44620

Ashkenazi Jewish (ASJ) AF: 0.0000386 AC: 1 AN: 25936

East Asian (EAS) AF: 0.00 AC: 0 AN: 39570

South Asian (SAS) AF: 0.000350 AC: 30 AN: 85618

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52238

Middle Eastern (MID) AF: 0.00926 AC: 53 AN: 5722

European-Non Finnish (NFE) AF: 0.000372 AC: 406 AN: 1090272

Other (OTH) AF: 0.0130 AC: 773 AN: 59574

GnomAD4 genome AF: 0.0574 AC: 8735 AN: 152272 Hom.: 869 Cov.: 33 AF XY: 0.0544 AC XY: 4048 AN XY: 74450

African (AFR) AF: 0.199 AC: 8280 AN: 41510

American (AMR) AF: 0.0208 AC: 319 AN: 15306

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.000621 AC: 3 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.0204 AC: 6 AN: 294

European-Non Finnish (NFE) AF: 0.000676 AC: 46 AN: 68030

Other (OTH) AF: 0.0383 AC: 81 AN: 2116

Alfa AF: 0.00415 Hom.: 7

Bravo AF: 0.0652

Asia WGS AF: 0.0140 AC: 50 AN: 3478

EpiCase AF: 0.000654

EpiControl AF: 0.000771

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	7.0
DANN	Benign	0.84
PhyloP100		0.28
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
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: rs1052012; hg19: chr14-74753107;