rs150346282

Variant names:

• chrX-153743031-G-A
• rs150346282
• NM_000033.4:c.1825G>A

Variant summary

Our verdict is Pathogenic. The variant received 22 ACMG points: 22P and 0B. PS3 PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_000033.4(ABCD1):​c.1825G>A​(p.Glu609Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000629996: Experimental studies have shown that this missense change affects ABCD1 function (PMID:21476988)." and additional evidence is available in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E609G) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 24)
  • Exomes 𝑓: 0.0 (0 hom. 0 hem.)
  • Failed GnomAD Quality Control
• Consequence: ABCD1 NM_000033.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:11
• Conservation: PhyloP100: 10.0
• Publications: 12 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 22 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000629996: Experimental studies have shown that this missense change affects ABCD1 function (PMID: 21476988).; SCV005340784: "In vitro experimental studies using patient fibroblasts suggest this variant results in the absence of protein (Table 4, Kemp et al. 2001. PubMed ID: 11748843; Table 1, Zhang et al. 2011. PubMed ID: 21476988)."
• PM1: In a hotspot region, there are 12 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 benign, 3 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-153743032-A-G is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 528345.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.964
• PP5: Variant X-153743031-G-A is Pathogenic according to our data. Variant chrX-153743031-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 166626.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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ABCD1	NM_000033.4	MANE Select	c.1825G>A	p.Glu609Lys	missense	Exon 8 of 10	NP_000024.2
	ABCD1	NM_001440747.1		c.2125G>A	p.Glu709Lys	missense	Exon 9 of 11	NP_001427676.1
	PLXNB3-AS1	NR_199693.1		n.90-4453C>T		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ABCD1	ENST00000218104.6	TSL:1 MANE Select	c.1825G>A	p.Glu609Lys	missense	Exon 8 of 10	ENSP00000218104.3	P33897
	ABCD1	ENST00000862307.1		c.2125G>A	p.Glu709Lys	missense	Exon 9 of 11	ENSP00000532366.1
	ABCD1	ENST00000862306.1		c.2095G>A	p.Glu699Lys	missense	Exon 9 of 11	ENSP00000532365.1

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD2 exomes AF: 0.00 AC: 0 AN: 161421 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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 1086846 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 355818

African (AFR) AF: 0.00 AC: 0 AN: 26230

American (AMR) AF: 0.00 AC: 0 AN: 34068

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19043

East Asian (EAS) AF: 0.00 AC: 0 AN: 29925

South Asian (SAS) AF: 0.00 AC: 0 AN: 52586

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39569

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2883

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 836974

Other (OTH) AF: 0.00 AC: 0 AN: 45568

GnomAD4 genome Cov.: 24

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ESP6500AA AF: 0.000261 AC: 1

ESP6500EA AF: 0.00 AC: 0

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
6	-	-	Adrenoleukodystrophy (6)
4	-	-	not provided (4)
1	-	-	ABCD1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.70	D
BayesDel_noAF	Pathogenic	0.77
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.98	D
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.91	D
M_CAP	Pathogenic	0.94	D
MetaRNN	Pathogenic	0.96	D
MetaSVM	Pathogenic	0.90	D
MutationAssessor	Pathogenic	4.3	H
PhyloP100		10
PrimateAI	Uncertain	0.69	T
PROVEAN	Uncertain	-3.2	D
REVEL	Pathogenic	0.95
Sift	Uncertain	0.022	D
Sift4G	Uncertain	0.024	D
Polyphen		1.0	D
Vest4		0.96
MVP		1.0
MPC		1.6
ClinPred		1.0	D
GERP RS		5.5
Varity_R		0.83
gMVP		1.0
Mutation Taster		=5/95	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
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: rs150346282; hg19: chrX-153008485;