1-94464789-G-A

Variant names:

• chr1-94464789-G-A
• rs16946
• NM_002858.4:c.162G>A

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_002858.4(ABCD3):​c.162G>A​(p.Lys54Lys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.445 in 1,610,872 control chromosomes in the GnomAD database, including 166,889 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.36 (11402 hom., cov: 29)
  • Exomes 𝑓: 0.45 (155487 hom.)
• Consequence: ABCD3 NM_002858.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 1.42
• Publications: 26 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: ClinGen, Ambry Genetics, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.43).
• BP6: Variant 1-94464789-G-A is Benign according to our data. Variant chr1-94464789-G-A is described in ClinVar as Benign. ClinVar VariationId is 258821.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.42 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.472 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002858.4. 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
	ABCD3	NM_002858.4	MANE Select	c.162G>A	p.Lys54Lys	synonymous	Exon 3 of 23	NP_002849.1	P28288-1
	ABCD3	NM_001122674.2		c.162G>A	p.Lys54Lys	synonymous	Exon 3 of 9	NP_001116146.1	P28288-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ABCD3	ENST00000370214.9	TSL:1 MANE Select	c.162G>A	p.Lys54Lys	synonymous	Exon 3 of 23	ENSP00000359233.4	P28288-1
	ABCD3	ENST00000315713.5	TSL:1	c.162G>A	p.Lys54Lys	synonymous	Exon 3 of 9	ENSP00000326880.5	P28288-3
	ABCD3	ENST00000866889.1		c.234G>A	p.Lys78Lys	synonymous	Exon 4 of 24	ENSP00000536948.1

Frequencies

GnomAD3 genomes AF: 0.361 AC: 54612 AN: 151410 Hom.: 11397 Cov.: 29

Gnomad AFR AF: 0.153

Gnomad AMI AF: 0.656

Gnomad AMR AF: 0.407

Gnomad ASJ AF: 0.439

Gnomad EAS AF: 0.214

Gnomad SAS AF: 0.347

Gnomad FIN AF: 0.367

Gnomad MID AF: 0.545

Gnomad NFE AF: 0.476

Gnomad OTH AF: 0.431

GnomAD2 exomes AF: 0.397 AC: 99653 AN: 251194 AF XY: 0.406

Gnomad AFR exome AF: 0.145

Gnomad AMR exome AF: 0.377

Gnomad ASJ exome AF: 0.451

Gnomad EAS exome AF: 0.207

Gnomad FIN exome AF: 0.368

Gnomad NFE exome AF: 0.476

Gnomad OTH exome AF: 0.445

GnomAD4 exome AF: 0.454 AC: 662421 AN: 1459344 Hom.: 155487 Cov.: 36 AF XY: 0.453 AC XY: 329024 AN XY: 726188

African (AFR) AF: 0.142 AC: 4751 AN: 33434

American (AMR) AF: 0.380 AC: 16983 AN: 44678

Ashkenazi Jewish (ASJ) AF: 0.449 AC: 11708 AN: 26104

East Asian (EAS) AF: 0.221 AC: 8754 AN: 39674

South Asian (SAS) AF: 0.372 AC: 32062 AN: 86166

European-Finnish (FIN) AF: 0.366 AC: 19543 AN: 53408

Middle Eastern (MID) AF: 0.540 AC: 3111 AN: 5762

European-Non Finnish (NFE) AF: 0.486 AC: 539008 AN: 1109784

Other (OTH) AF: 0.439 AC: 26501 AN: 60334

GnomAD4 genome AF: 0.361 AC: 54626 AN: 151528 Hom.: 11402 Cov.: 29 AF XY: 0.354 AC XY: 26236 AN XY: 74018

African (AFR) AF: 0.153 AC: 6329 AN: 41312

American (AMR) AF: 0.407 AC: 6186 AN: 15198

Ashkenazi Jewish (ASJ) AF: 0.439 AC: 1520 AN: 3466

East Asian (EAS) AF: 0.214 AC: 1097 AN: 5126

South Asian (SAS) AF: 0.349 AC: 1675 AN: 4798

European-Finnish (FIN) AF: 0.367 AC: 3831 AN: 10452

Middle Eastern (MID) AF: 0.552 AC: 160 AN: 290

European-Non Finnish (NFE) AF: 0.476 AC: 32345 AN: 67884

Other (OTH) AF: 0.424 AC: 889 AN: 2096

Alfa AF: 0.453 Hom.: 31638

Bravo AF: 0.359

Asia WGS AF: 0.257 AC: 896 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	Congenital bile acid synthesis defect 5 (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.43
CADD	Benign	4.3
DANN	Benign	0.60
PhyloP100		1.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs16946; hg19: chr1-94930345; COSMIC: COSV59866435;