rs3742801

chr14-74292303-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_005050.4(ABCD4):c.1102G>A(p.Glu368Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.349 in 1,613,546 control chromosomes in the GnomAD database, including 101,224 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.31 (7716 hom., cov: 32)
  • Exomes 𝑓: 0.35 (93508 hom.)
• Consequence: ABCD4 NM_005050.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.0780

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0028183162).
• BP6: Variant 14-74292303-C-T is Benign according to our data. Variant chr14-74292303-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 259619.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-74292303-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.366 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ABCD4	NM_005050.4	c.1102G>A	p.Glu368Lys	missense_variant	11/19	ENST00000356924.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ABCD4	ENST00000356924.9	c.1102G>A	p.Glu368Lys	missense_variant	11/19	1	NM_005050.4	P1
	ENST00000554532.2	n.1115+1008G>A		intron_variant, non_coding_transcript_variant		4

Frequencies

GnomAD3 genomes AF: 0.309 AC: 46891 AN: 151916 Hom.: 7725 Cov.: 32

Gnomad AFR AF: 0.191

Gnomad AMI AF: 0.467

Gnomad AMR AF: 0.306

Gnomad ASJ AF: 0.442

Gnomad EAS AF: 0.251

Gnomad SAS AF: 0.361

Gnomad FIN AF: 0.311

Gnomad MID AF: 0.560

Gnomad NFE AF: 0.370

Gnomad OTH AF: 0.363

GnomAD3 exomes AF: 0.327 AC: 82082 AN: 251102 Hom.: 14515 AF XY: 0.340 AC XY: 46137 AN XY: 135746

Gnomad AFR exome AF: 0.186

Gnomad AMR exome AF: 0.224

Gnomad ASJ exome AF: 0.437

Gnomad EAS exome AF: 0.242

Gnomad SAS exome AF: 0.367

Gnomad FIN exome AF: 0.310

Gnomad NFE exome AF: 0.372

Gnomad OTH exome AF: 0.372

GnomAD4 exome AF: 0.353 AC: 515495 AN: 1461512 Hom.: 93508 Cov.: 43 AF XY: 0.356 AC XY: 258752 AN XY: 727074

Gnomad4 AFR exome AF: 0.185

Gnomad4 AMR exome AF: 0.231

Gnomad4 ASJ exome AF: 0.444

Gnomad4 EAS exome AF: 0.242

Gnomad4 SAS exome AF: 0.371

Gnomad4 FIN exome AF: 0.314

Gnomad4 NFE exome AF: 0.364

Gnomad4 OTH exome AF: 0.360

GnomAD4 genome AF: 0.308 AC: 46888 AN: 152034 Hom.: 7716 Cov.: 32 AF XY: 0.306 AC XY: 22751 AN XY: 74306

Gnomad4 AFR AF: 0.191

Gnomad4 AMR AF: 0.305

Gnomad4 ASJ AF: 0.442

Gnomad4 EAS AF: 0.251

Gnomad4 SAS AF: 0.359

Gnomad4 FIN AF: 0.311

Gnomad4 NFE AF: 0.370

Gnomad4 OTH AF: 0.364

Alfa AF: 0.367 Hom.: 27530

Bravo AF: 0.300

TwinsUK AF: 0.366 AC: 1356

ALSPAC AF: 0.354 AC: 1365

ESP6500AA AF: 0.197 AC: 868

ESP6500EA AF: 0.364 AC: 3128

ExAC AF: 0.327 AC: 39739

Asia WGS AF: 0.311 AC: 1078 AN: 3478

EpiCase AF: 0.396

EpiControl AF: 0.404

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 02, 2015	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 03, 2021	- -

Methylmalonic acidemia with homocystinuria, type cblJ Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 14, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.085
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.13
Cadd	Benign	17
Dann	Uncertain	0.99
DEOGEN2	Benign	0.052	T
Eigen	Benign	-0.89
Eigen_PC	Benign	-0.77
FATHMM_MKL	Benign	0.066	N
LIST_S2	Benign	0.85	T
MetaRNN	Benign	0.0028	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.0	L
MutationTaster	Benign	1.0	P;P
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-0.66	N
REVEL	Uncertain	0.32
Sift	Benign	0.23	T
Sift4G	Benign	0.52	T
Polyphen		0.0020	B
Vest4		0.042
MPC		0.27
ClinPred		0.0080	T
GERP RS		1.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.043
gMVP		0.74

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

Publications

LitVar

Other links and lift over

dbSNP: rs3742801; hg19: chr14-74759006; COSMIC: COSV53991476; COSMIC: COSV53991476;