X-153743055-C-T

Variant names:

• chrX-153743055-C-T
• rs4010613
• NM_000033.4:c.1849C>T
• ABCD1 p.Arg617Cys

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.1849C>T​(p.Arg617Cys) variant causes a missense change. The variant allele was found at a frequency of 0.000000924 in 1,082,491 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 Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV001470865: functional studies of patient fibroblasts with this variant suggest loss of protein expression (Kemp 2001).". Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R617P) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 24)
  • Exomes 𝑓: 9.2e-7 (0 hom. 0 hem.)
• Consequence: ABCD1 NM_000033.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:11
• Conservation: PhyloP100: 4.70
• 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 22 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV001470865: functional studies of patient fibroblasts with this variant suggest loss of protein expression (Kemp 2001).
• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 7 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-153743056-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 2438749.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.996
• PP5: Variant X-153743055-C-T is Pathogenic according to our data. Variant chrX-153743055-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 11313.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.1849C>T	p.Arg617Cys	missense	Exon 8 of 10	NP_000024.2
	ABCD1	NM_001440747.1		c.2149C>T	p.Arg717Cys	missense	Exon 9 of 11	NP_001427676.1
	PLXNB3-AS1	NR_199693.1		n.90-4477G>A		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ABCD1	ENST00000218104.6	TSL:1 MANE Select	c.1849C>T	p.Arg617Cys	missense	Exon 8 of 10	ENSP00000218104.3	P33897
	ABCD1	ENST00000862307.1		c.2149C>T	p.Arg717Cys	missense	Exon 9 of 11	ENSP00000532366.1
	ABCD1	ENST00000862306.1		c.2119C>T	p.Arg707Cys	missense	Exon 9 of 11	ENSP00000532365.1

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome AF: 9.24e-7 AC: 1 AN: 1082491 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 352789

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

African (AFR) AF: 0.00 AC: 0 AN: 26174

American (AMR) AF: 0.00 AC: 0 AN: 33465

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18991

East Asian (EAS) AF: 0.00 AC: 0 AN: 29685

South Asian (SAS) AF: 0.00 AC: 0 AN: 52140

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39280

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2880

European-Non Finnish (NFE) AF: 0.00000120 AC: 1 AN: 834495

Other (OTH) AF: 0.00 AC: 0 AN: 45381

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 24

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
8	-	-	Adrenoleukodystrophy (8)
3	-	-	not provided (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.93
BayesDel_addAF	Pathogenic	0.68	D
BayesDel_noAF	Pathogenic	0.73
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.99	D
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Pathogenic	0.89	D
MetaRNN	Pathogenic	1.0	D
MetaSVM	Pathogenic	0.90	D
MutationAssessor	Uncertain	2.8	M
PhyloP100		4.7
PrimateAI	Uncertain	0.73	T
PROVEAN	Pathogenic	-6.4	D
REVEL	Pathogenic	0.96
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.91
gMVP		0.99
Mutation Taster		=14/86	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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs4010613;

hg19: chrX-153008509;