rs1557055340

Variant names:

• chrX-153743334-G-A
• rs1557055340
• NM_000033.4:c.1979G>A

Your query was ambiguous. Multiple possible variants found:

• chrX-153743334-G-A
• chrX-153743334-G-T

Variant summary

Our verdict is Pathogenic. The variant received 13 ACMG points: 13P and 0B. PS3 PM1 PM5 PP3_Strong PP5

The NM_000033.4(ABCD1):​c.1979G>A​(p.Arg660Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000466 in 1,073,117 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 2 hemizygotes in GnomAD. There is a variant allele frequency bias in the population database for this variant (GnomAdExome4), which may indicate mosaicism or somatic mutations in the reference population data. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). ClinVar reports functional evidence for this variant: "SCV002768864: "This variant has strong functional evidence supporting abnormal protein function. The adrenoleukodystrophy protein level was not detected via western blot (PMID:21966424)."". Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R660W) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0000047 (0 hom. 2 hem.)
• Consequence: ABCD1 NM_000033.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:7 U:2
• Conservation: PhyloP100: 9.92
• Publications: 2 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 13 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV002768864: "This variant has strong functional evidence supporting abnormal protein function. The adrenoleukodystrophy protein level was not detected via western blot (PMID: 21966424)."
• PM1: In a hotspot region, there are 11 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 11 uncertain in NM_000033.4
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrX-153743333-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 585302.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.954
• PP5: Variant X-153743334-G-A is Pathogenic according to our data. Variant chrX-153743334-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 632051.

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.1979G>A	p.Arg660Gln	missense	Exon 9 of 10	NP_000024.2
	ABCD1	NM_001440747.1		c.2279G>A	p.Arg760Gln	missense	Exon 10 of 11	NP_001427676.1
	PLXNB3-AS1	NR_199693.1		n.90-4756C>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.1979G>A	p.Arg660Gln	missense	Exon 9 of 10	ENSP00000218104.3	P33897
	ABCD1	ENST00000862307.1		c.2279G>A	p.Arg760Gln	missense	Exon 10 of 11	ENSP00000532366.1
	ABCD1	ENST00000862306.1		c.2249G>A	p.Arg750Gln	missense	Exon 10 of 11	ENSP00000532365.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD2 exomes AF: 0.00 AC: 0 AN: 138140 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 AF: 0.00000466 AC: 5 AN: 1073117 Hom.: 0 Cov.: 32 AF XY: 0.00000573 AC XY: 2 AN XY: 348777

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000386 AC: 1 AN: 25889

American (AMR) AF: 0.00 AC: 0 AN: 31450

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18901

East Asian (EAS) AF: 0.00 AC: 0 AN: 28846

South Asian (SAS) AF: 0.00 AC: 0 AN: 51264

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 38717

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2894

European-Non Finnish (NFE) AF: 0.00000482 AC: 4 AN: 830097

Other (OTH) AF: 0.00 AC: 0 AN: 45059

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000625500), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 23

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
6	1	-	Adrenoleukodystrophy (7)
1	1	-	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.69	D
BayesDel_noAF	Pathogenic	0.76
CADD	Pathogenic	31
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.90	D
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.87	D
MetaRNN	Pathogenic	0.95	D
MetaSVM	Pathogenic	0.92	D
MutationAssessor	Uncertain	2.3	M
PhyloP100		9.9
PrimateAI	Pathogenic	0.81	D
PROVEAN	Uncertain	-3.4	D
REVEL	Pathogenic	0.95
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0030	D
Polyphen		1.0	D
Vest4		0.96
MVP		1.0
MPC		1.6
ClinPred		1.0	D
GERP RS		4.7
Varity_R		0.79
gMVP		0.93
Mutation Taster		=4/96	disease causing (ClinVar)

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: rs1557055340; hg19: chrX-153008788; COSMIC: COSV54384478; COSMIC: COSV54384478;