X-153736195-C-T

Variant names:

• chrX-153736195-C-T
• rs128624215
• NM_000033.4:c.1165C>T

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.1165C>T​(p.Arg389Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000089 in 112,387 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R389H) has been classified as Likely pathogenic.

• Frequency: Genomes: 𝑓 0.0000089 (0 hom., 0 hem., cov: 24)
• Consequence: ABCD1 NM_000033.4 missense
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:6 U:1
• Conservation: PhyloP100: 2.24
• Publications: 6 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 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 13 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-153736196-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 281336.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.969
• PP5: Variant X-153736195-C-T is Pathogenic according to our data. Variant chrX-153736195-C-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 623115.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.1165C>T	p.Arg389Cys	missense	Exon 3 of 10	NP_000024.2
	ABCD1	NM_001440747.1		c.1165C>T	p.Arg389Cys	missense	Exon 3 of 11	NP_001427676.1
	PLXNB3-AS1	NR_199693.1		n.2473G>A		non_coding_transcript_exon	Exon 2 of 2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ABCD1	ENST00000218104.6	TSL:1 MANE Select	c.1165C>T	p.Arg389Cys	missense	Exon 3 of 10	ENSP00000218104.3	P33897
	ABCD1	ENST00000862307.1		c.1165C>T	p.Arg389Cys	missense	Exon 3 of 11	ENSP00000532366.1
	ABCD1	ENST00000862306.1		c.1165C>T	p.Arg389Cys	missense	Exon 3 of 11	ENSP00000532365.1

Frequencies

GnomAD3 genomes AF: 0.00000890 AC: 1 AN: 112387 Hom.: 0 Cov.: 24

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000188

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 34

GnomAD4 genome AF: 0.00000890 AC: 1 AN: 112387 Hom.: 0 Cov.: 24 AF XY: 0.00 AC XY: 0 AN XY: 34553

African (AFR) AF: 0.00 AC: 0 AN: 30933

American (AMR) AF: 0.00 AC: 0 AN: 10690

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2649

East Asian (EAS) AF: 0.00 AC: 0 AN: 3578

South Asian (SAS) AF: 0.00 AC: 0 AN: 2732

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6176

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 240

European-Non Finnish (NFE) AF: 0.0000188 AC: 1 AN: 53204

Other (OTH) AF: 0.00 AC: 0 AN: 1503

Alfa AF: 0.0000401 Hom.: 0

Bravo AF: 0.0000113

ESP6500AA AF: 0.000261 AC: 1

ESP6500EA AF: 0.00 AC: 0

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
5	1	-	Adrenoleukodystrophy (6)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.81
BayesDel_addAF	Pathogenic	0.67	D
BayesDel_noAF	Pathogenic	0.72
CADD	Uncertain	25
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.93	D
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Pathogenic	0.60	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.6	H
PhyloP100		2.2
PrimateAI	Uncertain	0.76	T
PROVEAN	Pathogenic	-6.9	D
REVEL	Pathogenic	0.89
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.91
MVP		1.0
MPC		1.7
ClinPred		1.0	D
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.66
gMVP		0.99
Mutation Taster		=11/89	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: rs128624215; hg19: chrX-153001649;