rs201455322

Variant names:

• chrX-153725973-G-A
• rs201455322
• NM_000033.4:c.707G>A

Your query was ambiguous. Multiple possible variants found:

• chrX-153725973-G-A
• chrX-153725973-G-T

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 2P and 13B. PM1 BP4_Strong BP6 BS1 BS2

The NM_000033.4(ABCD1):​c.707G>A​(p.Arg236His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000651 in 1,209,571 control chromosomes in the GnomAD database, including 4 homozygotes. There are 251 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R236C) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0012 (2 hom., 46 hem., cov: 26)
  • Exomes 𝑓: 0.00060 (2 hom. 205 hem.)
• Consequence: ABCD1 NM_000033.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:8
• Conservation: PhyloP100: 3.27
• Publications: 1 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: Benign. The variant received -11 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 4 benign, 12 uncertain in NM_000033.4
• BP4: Computational evidence support a benign effect (MetaRNN=0.018246949).
• BP6: Variant X-153725973-G-A is Benign according to our data. Variant chrX-153725973-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 193034.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00115 (131/113821) while in subpopulation AMR AF = 0.00486 (53/10900). AF 95% confidence interval is 0.00382. There are 2 homozygotes in GnomAd4. There are 46 alleles in the male GnomAd4 subpopulation. Median coverage is 26. This position passed quality control check.
• BS2: High AC in GnomAd4 at 131 XL,AD gene.

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.707G>A	p.Arg236His	missense	Exon 1 of 10	NP_000024.2
	ABCD1	NM_001440747.1		c.707G>A	p.Arg236His	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.707G>A	p.Arg236His	missense	Exon 1 of 10	ENSP00000218104.3	P33897
	ABCD1	ENST00000862307.1		c.707G>A	p.Arg236His	missense	Exon 1 of 11	ENSP00000532366.1
	ABCD1	ENST00000862306.1		c.707G>A	p.Arg236His	missense	Exon 1 of 11	ENSP00000532365.1

Frequencies

GnomAD3 genomes AF: 0.00115 AC: 131 AN: 113821 Hom.: 2 Cov.: 26

Gnomad AFR AF: 0.000127

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00486

Gnomad ASJ AF: 0.0229

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000348

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000187

Gnomad OTH AF: 0.00131

GnomAD2 exomes AF: 0.00142 AC: 254 AN: 178848 AF XY: 0.00125

Gnomad AFR exome AF: 0.0000783

Gnomad AMR exome AF: 0.00146

Gnomad ASJ exome AF: 0.0254

Gnomad EAS exome AF: 0.000147

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000163

Gnomad OTH exome AF: 0.00247

GnomAD4 exome AF: 0.000600 AC: 657 AN: 1095750 Hom.: 2 Cov.: 32 AF XY: 0.000566 AC XY: 205 AN XY: 362198

African (AFR) AF: 0.0000379 AC: 1 AN: 26395

American (AMR) AF: 0.00119 AC: 42 AN: 35188

Ashkenazi Jewish (ASJ) AF: 0.0224 AC: 433 AN: 19350

East Asian (EAS) AF: 0.0000662 AC: 2 AN: 30195

South Asian (SAS) AF: 0.0000185 AC: 1 AN: 54123

European-Finnish (FIN) AF: 0.0000260 AC: 1 AN: 38392

Middle Eastern (MID) AF: 0.000242 AC: 1 AN: 4136

European-Non Finnish (NFE) AF: 0.000115 AC: 97 AN: 841906

Other (OTH) AF: 0.00171 AC: 79 AN: 46065

GnomAD4 genome AF: 0.00115 AC: 131 AN: 113821 Hom.: 2 Cov.: 26 AF XY: 0.00128 AC XY: 46 AN XY: 35945

African (AFR) AF: 0.000127 AC: 4 AN: 31419

American (AMR) AF: 0.00486 AC: 53 AN: 10900

Ashkenazi Jewish (ASJ) AF: 0.0229 AC: 61 AN: 2666

East Asian (EAS) AF: 0.00 AC: 0 AN: 3614

South Asian (SAS) AF: 0.000348 AC: 1 AN: 2873

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6421

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

European-Non Finnish (NFE) AF: 0.000187 AC: 10 AN: 53468

Other (OTH) AF: 0.00131 AC: 2 AN: 1531

Alfa AF: 0.00151 Hom.: 56

Bravo AF: 0.00133

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.000261 AC: 1

ESP6500EA AF: 0.00119 AC: 8

ExAC AF: 0.00105 AC: 127

EpiCase AF: 0.000491

EpiControl AF: 0.000119

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	5	Adrenoleukodystrophy (6)
-	1	2	not provided (3)
-	-	1	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Uncertain	0.090	D
BayesDel_noAF	Pathogenic	0.33
CADD	Uncertain	24
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.91	D
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Benign	0.81	T
M_CAP	Pathogenic	0.72	D
MetaRNN	Benign	0.018	T
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Benign	2.0	M
PhyloP100		3.3
PrimateAI	Uncertain	0.75	T
PROVEAN	Uncertain	-3.0	D
REVEL	Pathogenic	0.76
Sift	Uncertain	0.025	D
Sift4G	Benign	0.073	T
Polyphen		1.0	D
Vest4		0.44
MVP		1.0
MPC		1.7
ClinPred		0.064	T
GERP RS		5.4
PromoterAI		0.019	Neutral
Varity_R		0.20
gMVP		0.56
Mutation Taster		=69/31	polymorphism (auto)

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: rs201455322; hg19: chrX-152991428;