rs1052022

Variant names:

• chr14-74286341-T-C
• rs1052022
• NM_005050.4:c.*120A>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.*120A>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 0.00651 in 1,065,298 control chromosomes in the GnomAD database, including 282 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.027 (174 hom., cov: 33)
  • Exomes 𝑓: 0.0030 (108 hom.)
• Consequence: ABCD4 NM_005050.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.342
• Publications: 1 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: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet, ClinGen

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 14-74286341-T-C is Benign according to our data. Variant chr14-74286341-T-C is described in ClinVar as Benign. ClinVar VariationId is 1174281.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0926 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.*120A>G		3_prime_UTR	Exon 19 of 19	NP_005041.1	O14678
	ABCD4	NM_020325.3		c.*333A>G		3_prime_UTR	Exon 18 of 18	NP_064730.1
	ABCD4	NM_001440752.1		c.*449A>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.*120A>G		3_prime_UTR	Exon 19 of 19	ENSP00000349396.4	O14678
	ABCD4	ENST00000885459.1		c.*120A>G		3_prime_UTR	Exon 19 of 19	ENSP00000555518.1
	ABCD4	ENST00000885453.1		c.*120A>G		3_prime_UTR	Exon 19 of 19	ENSP00000555512.1

Frequencies

GnomAD3 genomes AF: 0.0272 AC: 4144 AN: 152190 Hom.: 174 Cov.: 33

Gnomad AFR AF: 0.0951

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00988

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000162

Gnomad OTH AF: 0.0186

GnomAD4 exome AF: 0.00305 AC: 2781 AN: 912990 Hom.: 108 Cov.: 12 AF XY: 0.00265 AC XY: 1253 AN XY: 473172

African (AFR) AF: 0.0937 AC: 2161 AN: 23058

American (AMR) AF: 0.00509 AC: 207 AN: 40694

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 20714

East Asian (EAS) AF: 0.00 AC: 0 AN: 37076

South Asian (SAS) AF: 0.000228 AC: 16 AN: 70180

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40088

Middle Eastern (MID) AF: 0.00367 AC: 17 AN: 4636

European-Non Finnish (NFE) AF: 0.000120 AC: 76 AN: 634294

Other (OTH) AF: 0.00720 AC: 304 AN: 42250

GnomAD4 genome AF: 0.0273 AC: 4156 AN: 152308 Hom.: 174 Cov.: 33 AF XY: 0.0260 AC XY: 1935 AN XY: 74484

African (AFR) AF: 0.0951 AC: 3952 AN: 41554

American (AMR) AF: 0.00987 AC: 151 AN: 15306

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000162 AC: 11 AN: 68020

Other (OTH) AF: 0.0184 AC: 39 AN: 2116

Alfa AF: 0.0124 Hom.: 34

Bravo AF: 0.0309

Asia WGS AF: 0.00549 AC: 19 AN: 3478

ClinVar

ClinVar submissions as Germline

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	-0.89
CADD	Benign	3.7
DANN	Benign	0.59
PhyloP100		0.34
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: rs1052022; hg19: chr14-74753044;