NM_000033.4:c.796G>A

Variant names:

• chrX-153726062-G-A
• rs128624218
• NM_000033.4:c.796G>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.796G>A​(p.Gly266Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000925 in 1,081,351 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. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV001553869: The variant did not have any effect on protein stability in experimental study by Kawaguchi (2016) indicating that this amino acid residue is likely critical for the protein function as it was one of the most common ABCD1 mutations seen in patients with ALD in the literature. PMID:27546972". Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G266W) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 26)
  • Exomes 𝑓: 9.2e-7 (0 hom. 0 hem.)
• Consequence: ABCD1 NM_000033.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:12
• Conservation: PhyloP100: 9.58
• Publications: 19 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]

BCAP31 (HGNC:16695): (B cell receptor associated protein 31) This gene encodes a member of the B-cell receptor associated protein 31 superfamily. The encoded protein is a multi-pass transmembrane protein of the endoplasmic reticulum that is involved in the anterograde transport of membrane proteins from the endoplasmic reticulum to the Golgi and in caspase 8-mediated apoptosis. Microdeletions in this gene are associated with contiguous ABCD1/DXS1375E deletion syndrome (CADDS), a neonatal disorder. Alternative splicing of this gene results in multiple transcript variants. Two related pseudogenes have been identified on chromosome 16. [provided by RefSeq, Jan 2012]

BCAP31 Gene-Disease associations (from GenCC):

• severe motor and intellectual disabilities-sensorineural deafness-dystonia syndrome

  Inheritance: AR, XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, ClinGen, G2P, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Pathogenic. The variant received 22 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV001553869: The variant did not have any effect on protein stability in experimental study by Kawaguchi (2016) indicating that this amino acid residue is likely critical for the protein function as it was one of the most common ABCD1 mutations seen in patients with ALD in the literature. PMID:27546972
• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 16 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-153726062-G-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 1521570.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.993
• PP5: Variant X-153726062-G-A is Pathogenic according to our data. Variant chrX-153726062-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 11299.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.796G>A	p.Gly266Arg	missense	Exon 1 of 10	NP_000024.2
	ABCD1	NM_001440747.1		c.796G>A	p.Gly266Arg	missense	Exon 1 of 11	NP_001427676.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ABCD1	ENST00000218104.6	TSL:1 MANE Select	c.796G>A	p.Gly266Arg	missense	Exon 1 of 10	ENSP00000218104.3	P33897
	ABCD1	ENST00000862307.1		c.796G>A	p.Gly266Arg	missense	Exon 1 of 11	ENSP00000532366.1
	ABCD1	ENST00000862306.1		c.796G>A	p.Gly266Arg	missense	Exon 1 of 11	ENSP00000532365.1

Frequencies

GnomAD3 genomes Cov.: 26

GnomAD4 exome AF: 9.25e-7 AC: 1 AN: 1081351 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 350685

African (AFR) AF: 0.00 AC: 0 AN: 26050

American (AMR) AF: 0.00 AC: 0 AN: 33679

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18628

East Asian (EAS) AF: 0.00 AC: 0 AN: 29640

South Asian (SAS) AF: 0.00 AC: 0 AN: 51847

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 38758

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4092

European-Non Finnish (NFE) AF: 0.00000120 AC: 1 AN: 833260

Other (OTH) AF: 0.00 AC: 0 AN: 45397

GnomAD4 genome Cov.: 26

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
7	-	-	Adrenoleukodystrophy (7)
3	-	-	not provided (3)
1	-	-	Inborn genetic diseases (1)
1	-	-	X-linked spondyloepimetaphyseal dysplasia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.93
BayesDel_addAF	Pathogenic	0.66	D
BayesDel_noAF	Pathogenic	0.71
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.98	D
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Pathogenic	0.77	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.5	H
PhyloP100		9.6
PrimateAI	Pathogenic	0.88	D
PROVEAN	Pathogenic	-7.6	D
REVEL	Pathogenic	0.98
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.84
MutPred		0.94		Gain of MoRF binding (P = 0.0171)
MVP		1.0
MPC		1.7
ClinPred		1.0	D
GERP RS		5.4
PromoterAI		-0.016	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.99
gMVP		0.94
Mutation Taster		=0/100	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: rs128624218; hg19: chrX-152991517;