1-94418439-C-T

Variant names:

• chr1-94418439-C-T
• rs4148058
• NM_002858.4:c.-40C>T

Variant summary

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

The NM_002858.4(ABCD3):​c.-40C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0408 in 1,546,526 control chromosomes in the GnomAD database, including 2,018 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 0.033 (162 hom., cov: 33)
  • Exomes 𝑓: 0.042 (1856 hom.)
• Consequence: ABCD3 NM_002858.4 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.25
• Publications: 4 publications found

Genes affected

ABCD3 (HGNC:67): (ATP binding cassette subfamily D member 3) 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. This peroxisomal membrane protein likely plays an important role in peroxisome biogenesis. Mutations have been associated with some forms of Zellweger syndrome, a heterogeneous group of peroxisome assembly disorders. Alternative splicing results in multiple transcript variants encoding distinct isoforms. [provided by RefSeq, Jul 2008]

ABCD3 Gene-Disease associations (from GenCC):

• congenital bile acid synthesis defect 5

  Inheritance: AR, Unknown Classification: LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), ClinGen

ENSG00000286692 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.169 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ABCD3	NM_002858.4	c.-40C>T		5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 23	ENST00000370214.9	NP_002849.1
ABCD3	NM_002858.4	c.-40C>T		5_prime_UTR_variant	Exon 1 of 23	ENST00000370214.9	NP_002849.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ABCD3	ENST00000370214.9	c.-40C>T		5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 23	1	NM_002858.4	ENSP00000359233.4
ABCD3	ENST00000370214.9	c.-40C>T		5_prime_UTR_variant	Exon 1 of 23	1	NM_002858.4	ENSP00000359233.4

Frequencies

GnomAD3 genomes AF: 0.0325 AC: 4946 AN: 152072 Hom.: 160 Cov.: 33

Gnomad AFR AF: 0.00659

Gnomad AMI AF: 0.0143

Gnomad AMR AF: 0.0327

Gnomad ASJ AF: 0.0695

Gnomad EAS AF: 0.178

Gnomad SAS AF: 0.0447

Gnomad FIN AF: 0.0360

Gnomad MID AF: 0.0510

Gnomad NFE AF: 0.0343

Gnomad OTH AF: 0.0273

GnomAD2 exomes AF: 0.0479 AC: 8466 AN: 176638 AF XY: 0.0475

Gnomad AFR exome AF: 0.00528

Gnomad AMR exome AF: 0.0379

Gnomad ASJ exome AF: 0.0604

Gnomad EAS exome AF: 0.177

Gnomad FIN exome AF: 0.0352

Gnomad NFE exome AF: 0.0365

Gnomad OTH exome AF: 0.0361

GnomAD4 exome AF: 0.0417 AC: 58188 AN: 1394338 Hom.: 1856 Cov.: 27 AF XY: 0.0420 AC XY: 29117 AN XY: 692802

African (AFR) AF: 0.00603 AC: 191 AN: 31700

American (AMR) AF: 0.0358 AC: 1437 AN: 40190

Ashkenazi Jewish (ASJ) AF: 0.0644 AC: 1636 AN: 25386

East Asian (EAS) AF: 0.198 AC: 7298 AN: 36834

South Asian (SAS) AF: 0.0463 AC: 3783 AN: 81642

European-Finnish (FIN) AF: 0.0356 AC: 1357 AN: 38138

Middle Eastern (MID) AF: 0.0433 AC: 207 AN: 4786

European-Non Finnish (NFE) AF: 0.0369 AC: 39780 AN: 1077548

Other (OTH) AF: 0.0430 AC: 2499 AN: 58114

GnomAD4 genome AF: 0.0325 AC: 4949 AN: 152188 Hom.: 162 Cov.: 33 AF XY: 0.0342 AC XY: 2549 AN XY: 74430

African (AFR) AF: 0.00657 AC: 273 AN: 41548

American (AMR) AF: 0.0327 AC: 500 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0695 AC: 241 AN: 3468

East Asian (EAS) AF: 0.179 AC: 920 AN: 5144

South Asian (SAS) AF: 0.0449 AC: 217 AN: 4828

European-Finnish (FIN) AF: 0.0360 AC: 382 AN: 10600

Middle Eastern (MID) AF: 0.0514 AC: 15 AN: 292

European-Non Finnish (NFE) AF: 0.0342 AC: 2327 AN: 67988

Other (OTH) AF: 0.0289 AC: 61 AN: 2112

Alfa AF: 0.0204 Hom.: 13

Bravo AF: 0.0315

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	3.9
DANN	Benign	0.83
PhyloP100		-1.3
PromoterAI		-0.0024	Neutral
Mutation Taster		=300/0	polymorphism (auto)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs4148058; hg19: chr1-94883995; COSMIC: COSV59867890;