rs398123102

Variant names:

• chrX-153740156-G-A
• rs398123102
• NM_000033.4:c.1553G>A

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_000033.4(ABCD1):​c.1553G>A​(p.Arg518Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000912 in 1,096,719 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R518W) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 24)
  • Exomes 𝑓: 9.1e-7 (0 hom. 0 hem.)
• Consequence: ABCD1 NM_000033.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:13
• Conservation: PhyloP100: 10.0
• Publications: 11 publications found

Genes affected

ABCD1 (HGNC:61): (ATP binding cassette subfamily D member 1) 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 is likely involved in the peroxisomal transport or catabolism of very long chain fatty acids. Defects in this gene have been identified as the underlying cause of adrenoleukodystrophy, an X-chromosome recessively inherited demyelinating disorder of the nervous system. [provided by RefSeq, Jul 2008]

PLXNB3-AS1 (HGNC:40454): (PLXNB3 antisense RNA 1)

ACMG classification

Our verdict: Pathogenic. The variant received 18 ACMG points.

• PM1: In a hotspot region, there are 15 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in NM_000033.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrX-153740155-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 11307.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.994
• PP5: Variant X-153740156-G-A is Pathogenic according to our data. Variant chrX-153740156-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 92317.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000033.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ABCD1	NM_000033.4	MANE Select	c.1553G>A	p.Arg518Gln	missense	Exon 6 of 10	NP_000024.2
	ABCD1	NM_001440747.1		c.1853G>A	p.Arg618Gln	missense	Exon 7 of 11	NP_001427676.1
	PLXNB3-AS1	NR_199693.1		n.90-1578C>T		intron	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ABCD1	ENST00000218104.6	TSL:1 MANE Select	c.1553G>A	p.Arg518Gln	missense	Exon 6 of 10	ENSP00000218104.3
	ABCD1	ENST00000443684.2	TSL:3	n.556G>A		non_coding_transcript_exon	Exon 5 of 6
	PLXNB3-AS1	ENST00000434284.1	TSL:3	n.72-1578C>T		intron	N/A

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD2 exomes AF: 0.00000548 AC: 1 AN: 182400 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000123

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 9.12e-7 AC: 1 AN: 1096719 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 362213

African (AFR) AF: 0.00 AC: 0 AN: 26384

American (AMR) AF: 0.00 AC: 0 AN: 35141

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19339

East Asian (EAS) AF: 0.00 AC: 0 AN: 30160

South Asian (SAS) AF: 0.00 AC: 0 AN: 54027

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40421

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4129

European-Non Finnish (NFE) AF: 0.00000119 AC: 1 AN: 841110

Other (OTH) AF: 0.00 AC: 0 AN: 46008

GnomAD4 genome Cov.: 24

Alfa AF: 0.00 Hom.: 0

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.00

EpiControl AF: 0.0000594

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
7	-	-	Adrenoleukodystrophy (7)
5	-	-	not provided (5)
1	-	-	ABCD1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Pathogenic	0.68	D
BayesDel_noAF	Pathogenic	0.74
CADD	Pathogenic	30
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.96	D
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.87	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	0.93	D
MutationAssessor	Uncertain	2.2	M
PhyloP100		10
PrimateAI	Uncertain	0.60	T
PROVEAN	Uncertain	-3.6	D
REVEL	Pathogenic	0.94
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.81
MutPred		0.97		Gain of methylation at K513 (P = 0.0396)
MVP		1.0
MPC		1.6
ClinPred		0.95	D
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.90
gMVP		0.92
Mutation Taster		=20/80	disease causing (ClinVar)

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: rs398123102; hg19: chrX-153005610; COSMIC: COSV106089412;