rs782693577

Variant names:

• chrX-153725316-G-A
• rs782693577
• NM_000033.4:c.50G>A
• ABCD1 p.Arg17His

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP6_Very_Strong BS2

The NM_000033.4(ABCD1):​c.50G>A​(p.Arg17His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000117 in 1,149,123 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 42 hemizygotes in GnomAD. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00012 (0 hom., 4 hem., cov: 25)
  • Exomes 𝑓: 0.00012 (0 hom. 38 hem.)
• Consequence: ABCD1 NM_000033.4 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 2.80
• Publications: 3 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, G2P, ClinGen, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP6: Variant X-153725316-G-A is Benign according to our data. Variant chrX-153725316-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 583372.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 13 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.50G>A	p.Arg17His	missense	Exon 1 of 10	NP_000024.2
	ABCD1	NM_001440747.1		c.50G>A	p.Arg17His	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.50G>A	p.Arg17His	missense	Exon 1 of 10	ENSP00000218104.3	P33897
	ABCD1	ENST00000862307.1		c.50G>A	p.Arg17His	missense	Exon 1 of 11	ENSP00000532366.1
	ABCD1	ENST00000862306.1		c.50G>A	p.Arg17His	missense	Exon 1 of 11	ENSP00000532365.1

Frequencies

GnomAD3 genomes AF: 0.000115 AC: 13 AN: 113002 Hom.: 0 Cov.: 25

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: 0.000244

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000795 AC: 7 AN: 88054 AF XY: 0.0000768

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000217

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000118 AC: 122 AN: 1036121 Hom.: 0 Cov.: 32 AF XY: 0.000114 AC XY: 38 AN XY: 333847

African (AFR) AF: 0.00 AC: 0 AN: 24297

American (AMR) AF: 0.00 AC: 0 AN: 26685

Ashkenazi Jewish (ASJ) AF: 0.0000552 AC: 1 AN: 18107

East Asian (EAS) AF: 0.000150 AC: 4 AN: 26729

South Asian (SAS) AF: 0.00 AC: 0 AN: 48592

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 31927

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3030

European-Non Finnish (NFE) AF: 0.000140 AC: 114 AN: 813071

Other (OTH) AF: 0.0000687 AC: 3 AN: 43683

GnomAD4 genome AF: 0.000115 AC: 13 AN: 113002 Hom.: 0 Cov.: 25 AF XY: 0.000114 AC XY: 4 AN XY: 35148

African (AFR) AF: 0.00 AC: 0 AN: 31176

American (AMR) AF: 0.00 AC: 0 AN: 10874

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2654

East Asian (EAS) AF: 0.00 AC: 0 AN: 3558

South Asian (SAS) AF: 0.00 AC: 0 AN: 2833

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6276

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

European-Non Finnish (NFE) AF: 0.000244 AC: 13 AN: 53189

Other (OTH) AF: 0.00 AC: 0 AN: 1524

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.000102

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.040
CADD	Uncertain	24
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.80	D
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.85	D
M_CAP	Pathogenic	0.41	D
MetaRNN	Uncertain	0.61	D
MetaSVM	Uncertain	0.49	D
MutationAssessor	Benign	0.81	L
PhyloP100		2.8
PrimateAI	Uncertain	0.73	T
PROVEAN	Benign	-2.2	N
REVEL	Uncertain	0.48
Sift	Uncertain	0.015	D
Sift4G	Uncertain	0.015	D
PromoterAI		-0.055	Neutral
Varity_R		0.35
gMVP		0.27
Mutation Taster		=84/16	polymorphism

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: rs782693577;

hg19: chrX-152990771;