chr14-74286199-A-C

Variant names:

• chr14-74286199-A-C
• rs2466
• NM_005050.4:c.*262T>G

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.*262T>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.165 in 393,800 control chromosomes in the GnomAD database, including 7,417 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.18 (3212 hom., cov: 33)
  • Exomes 𝑓: 0.16 (4205 hom.)
• Consequence: ABCD4 NM_005050.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.269
• Publications: 13 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 (BayesDel_noAF=-0.88).
• BP6: Variant 14-74286199-A-C is Benign according to our data. Variant chr14-74286199-A-C is described in ClinVar as Benign. ClinVar VariationId is 1262596.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.471 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.*262T>G		3_prime_UTR	Exon 19 of 19	NP_005041.1	O14678
	ABCD4	NM_020325.3		c.*475T>G		3_prime_UTR	Exon 18 of 18	NP_064730.1
	ABCD4	NM_001440752.1		c.*591T>G		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.*262T>G		3_prime_UTR	Exon 19 of 19	ENSP00000349396.4	O14678
	ABCD4	ENST00000885459.1		c.*262T>G		3_prime_UTR	Exon 19 of 19	ENSP00000555518.1
	ABCD4	ENST00000885453.1		c.*262T>G		3_prime_UTR	Exon 19 of 19	ENSP00000555512.1

Frequencies

GnomAD3 genomes AF: 0.179 AC: 27228 AN: 152004 Hom.: 3203 Cov.: 33

Gnomad AFR AF: 0.291

Gnomad AMI AF: 0.0318

Gnomad AMR AF: 0.139

Gnomad ASJ AF: 0.166

Gnomad EAS AF: 0.487

Gnomad SAS AF: 0.182

Gnomad FIN AF: 0.0761

Gnomad MID AF: 0.185

Gnomad NFE AF: 0.115

Gnomad OTH AF: 0.193

GnomAD4 exome AF: 0.155 AC: 37518 AN: 241676 Hom.: 4205 Cov.: 0 AF XY: 0.155 AC XY: 19301 AN XY: 124742

African (AFR) AF: 0.290 AC: 2165 AN: 7456

American (AMR) AF: 0.147 AC: 1310 AN: 8916

Ashkenazi Jewish (ASJ) AF: 0.164 AC: 1320 AN: 8072

East Asian (EAS) AF: 0.455 AC: 8481 AN: 18654

South Asian (SAS) AF: 0.172 AC: 2587 AN: 15004

European-Finnish (FIN) AF: 0.0850 AC: 1388 AN: 16334

Middle Eastern (MID) AF: 0.180 AC: 199 AN: 1108

European-Non Finnish (NFE) AF: 0.116 AC: 17505 AN: 150940

Other (OTH) AF: 0.169 AC: 2563 AN: 15192

GnomAD4 genome AF: 0.179 AC: 27272 AN: 152124 Hom.: 3212 Cov.: 33 AF XY: 0.179 AC XY: 13300 AN XY: 74364

African (AFR) AF: 0.291 AC: 12087 AN: 41482

American (AMR) AF: 0.139 AC: 2131 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.166 AC: 575 AN: 3472

East Asian (EAS) AF: 0.487 AC: 2503 AN: 5140

South Asian (SAS) AF: 0.183 AC: 884 AN: 4820

European-Finnish (FIN) AF: 0.0761 AC: 806 AN: 10594

Middle Eastern (MID) AF: 0.184 AC: 54 AN: 294

European-Non Finnish (NFE) AF: 0.115 AC: 7793 AN: 68008

Other (OTH) AF: 0.194 AC: 410 AN: 2110

Alfa AF: 0.136 Hom.: 2469

Bravo AF: 0.193

Asia WGS AF: 0.311 AC: 1078 AN: 3478

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	-0.88
CADD	Benign	0.33
DANN	Benign	0.62
PhyloP100		-0.27
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: rs2466; hg19: chr14-74752902;