rs183021839

Variant names:

• chrX-153725304-A-C
• rs183021839
• NM_000033.4:c.38A>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000033.4(ABCD1):​c.38A>C​(p.Asn13Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00264 in 1,146,578 control chromosomes in the GnomAD database, including 6 homozygotes. There are 979 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0022 (0 hom., 90 hem., cov: 25)
  • Exomes 𝑓: 0.0027 (6 hom. 889 hem.)
• Consequence: ABCD1 NM_000033.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -0.0820
• 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]

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.00509429).
• BP6: Variant X-153725304-A-C is Benign according to our data. Variant chrX-153725304-A-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 368044.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00222 (251/112855) while in subpopulation NFE AF = 0.00316 (168/53087). AF 95% confidence interval is 0.00277. There are 0 homozygotes in GnomAd4. There are 90 alleles in the male GnomAd4 subpopulation. Median coverage is 25. This position passed quality control check.
• BS2: High AC in GnomAd4 at 251 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.38A>C	p.Asn13Thr	missense	Exon 1 of 10	NP_000024.2
	ABCD1	NM_001440747.1		c.38A>C	p.Asn13Thr	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.38A>C	p.Asn13Thr	missense	Exon 1 of 10	ENSP00000218104.3	P33897
	ABCD1	ENST00000862307.1		c.38A>C	p.Asn13Thr	missense	Exon 1 of 11	ENSP00000532366.1
	ABCD1	ENST00000862306.1		c.38A>C	p.Asn13Thr	missense	Exon 1 of 11	ENSP00000532365.1

Frequencies

GnomAD3 genomes AF: 0.00223 AC: 251 AN: 112804 Hom.: 0 Cov.: 25

Gnomad AFR AF: 0.000192

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000368

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0117

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00316

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00203 AC: 174 AN: 85534 AF XY: 0.00169

Gnomad AFR exome AF: 0.000215

Gnomad AMR exome AF: 0.000932

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0111

Gnomad NFE exome AF: 0.00238

Gnomad OTH exome AF: 0.00341

GnomAD4 exome AF: 0.00268 AC: 2772 AN: 1033723 Hom.: 6 Cov.: 32 AF XY: 0.00267 AC XY: 889 AN XY: 332361

African (AFR) AF: 0.000372 AC: 9 AN: 24167

American (AMR) AF: 0.000683 AC: 18 AN: 26347

Ashkenazi Jewish (ASJ) AF: 0.000111 AC: 2 AN: 17996

East Asian (EAS) AF: 0.00 AC: 0 AN: 26636

South Asian (SAS) AF: 0.00 AC: 0 AN: 48286

European-Finnish (FIN) AF: 0.0120 AC: 378 AN: 31531

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3002

European-Non Finnish (NFE) AF: 0.00282 AC: 2292 AN: 812172

Other (OTH) AF: 0.00167 AC: 73 AN: 43586

GnomAD4 genome AF: 0.00222 AC: 251 AN: 112855 Hom.: 0 Cov.: 25 AF XY: 0.00257 AC XY: 90 AN XY: 35065

African (AFR) AF: 0.000192 AC: 6 AN: 31241

American (AMR) AF: 0.000367 AC: 4 AN: 10893

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2642

East Asian (EAS) AF: 0.00 AC: 0 AN: 3524

South Asian (SAS) AF: 0.00 AC: 0 AN: 2791

European-Finnish (FIN) AF: 0.0117 AC: 73 AN: 6239

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 219

European-Non Finnish (NFE) AF: 0.00316 AC: 168 AN: 53087

Other (OTH) AF: 0.00 AC: 0 AN: 1543

Alfa AF: 0.00406 Hom.: 48

Bravo AF: 0.00117

TwinsUK AF: 0.00162 AC: 6

ALSPAC AF: 0.000692 AC: 2

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000531 AC: 3

ExAC AF: 0.000619 AC: 38

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.067
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.64
CADD	Benign	0.26
DANN	Benign	0.29
DEOGEN2	Benign	0.34	T
FATHMM_MKL	Benign	0.095	N
LIST_S2	Benign	0.24	T
MetaRNN	Benign	0.0051	T
MetaSVM	Benign	-0.51	T
MutationAssessor	Benign	-0.69	N
PhyloP100		-0.082
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	0.030	N
REVEL	Benign	0.26
Sift	Benign	1.0	T
Sift4G	Benign	0.61	T
Polyphen		0.0	B
Vest4		0.058
MVP		0.55
MPC		0.57
ClinPred		0.0017	T
GERP RS		3.3
PromoterAI		0.018	Neutral
Varity_R		0.055
gMVP		0.21
Mutation Taster		=95/5	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: rs183021839; hg19: chrX-152990759;