rs45568335

chr14-74290035-G-A

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 1P and 9B. PP3 BP6 BS1 BS2

The NM_005050.4(ABCD4):c.1411C>T(p.Arg471Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00191 in 1,614,138 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0016 (1 hom., cov: 31)
  • Exomes 𝑓: 0.0019 (10 hom.)
• Consequence: ABCD4 NM_005050.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:4
• Conservation: PhyloP100: 3.03

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 -8 ACMG points.

• PP3: Multiple lines of computational evidence support a deleterious effect 8: AlphaMissense, BayesDel_noAF, Cadd, Dann, Eigen, PrimateAI, PROVEAN, REVEL [when FATHMM_MKL, MetaRNN, MutationTaster, phyloP100way_vertebrate was below the threshold]
• BP6: Variant 14-74290035-G-A is Benign according to our data. Variant chr14-74290035-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 381876.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Uncertain_significance=2}. Variant chr14-74290035-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00164 (249/152254) while in subpopulation AMR AF= 0.00262 (40/15296). AF 95% confidence interval is 0.00199. There are 1 homozygotes in gnomad4. There are 130 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ABCD4	NM_005050.4	c.1411C>T	p.Arg471Trp	missense_variant	13/19	ENST00000356924.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ABCD4	ENST00000356924.9	c.1411C>T	p.Arg471Trp	missense_variant	13/19	1	NM_005050.4	P1
	ENST00000554532.2	n.1116-657C>T		intron_variant, non_coding_transcript_variant		4

Frequencies

GnomAD3 genomes AF: 0.00164 AC: 249 AN: 152136 Hom.: 1 Cov.: 31

Gnomad AFR AF: 0.000652

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00262

Gnomad ASJ AF: 0.00259

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.000659

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00228

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.00155 AC: 390 AN: 251442 Hom.: 5 AF XY: 0.00158 AC XY: 215 AN XY: 135902

Gnomad AFR exome AF: 0.000554

Gnomad AMR exome AF: 0.00142

Gnomad ASJ exome AF: 0.00208

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000980

Gnomad FIN exome AF: 0.000508

Gnomad NFE exome AF: 0.00222

Gnomad OTH exome AF: 0.00293

GnomAD4 exome AF: 0.00194 AC: 2838 AN: 1461884 Hom.: 10 Cov.: 33 AF XY: 0.00188 AC XY: 1368 AN XY: 727244

Gnomad4 AFR exome AF: 0.000568

Gnomad4 AMR exome AF: 0.00159

Gnomad4 ASJ exome AF: 0.00241

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000800

Gnomad4 FIN exome AF: 0.000768

Gnomad4 NFE exome AF: 0.00219

Gnomad4 OTH exome AF: 0.00169

GnomAD4 genome AF: 0.00164 AC: 249 AN: 152254 Hom.: 1 Cov.: 31 AF XY: 0.00175 AC XY: 130 AN XY: 74446

Gnomad4 AFR AF: 0.000650

Gnomad4 AMR AF: 0.00262

Gnomad4 ASJ AF: 0.00259

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00104

Gnomad4 FIN AF: 0.000659

Gnomad4 NFE AF: 0.00228

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.00184 Hom.: 1

Bravo AF: 0.00171

TwinsUK AF: 0.00189 AC: 7

ALSPAC AF: 0.00259 AC: 10

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00140 AC: 12

ExAC AF: 0.00168 AC: 204

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00240

EpiControl AF: 0.00196

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Methylmalonic acidemia with homocystinuria, type cblJ Uncertain:1 Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 31, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 30, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

not provided Uncertain:1 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 29, 2020	Has not been previously published as pathogenic or benign to our knowledge; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 20849526) -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2023	ABCD4: PP3, BS2 -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jan 06, 2023	BS1, PP3 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.65
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Pathogenic	0.43
Cadd	Pathogenic	34
Dann	Pathogenic	1.0
DEOGEN2	Uncertain	0.62	D
Eigen	Pathogenic	0.74
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.94	D
M_CAP	Uncertain	0.19	D
MetaRNN	Benign	0.20	T
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Uncertain	2.8	M
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.84	D
PROVEAN	Pathogenic	-5.5	D
REVEL	Pathogenic	0.89
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.96
MVP		0.99
MPC		0.90
ClinPred		0.040	T
GERP RS		5.8
Varity_R		0.72
gMVP		0.93

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.24		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.24		Position offset: -8

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

Publications

LitVar

Other links and lift over

dbSNP: rs45568335; hg19: chr14-74756738;