rs41302176

Variant names:

• chrX-153729216-C-T
• rs41302176
• NM_000033.4:c.901-16C>T

Variant summary

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

The NM_001440747.1(ABCD1):​c.901-16C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0112 in 1,210,356 control chromosomes in the GnomAD database, including 87 homozygotes. There are 4,322 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0081 (5 hom., 252 hem., cov: 23)
  • Exomes 𝑓: 0.012 (82 hom. 4070 hem.)
• Consequence: ABCD1 NM_001440747.1 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.0110
• Publications: 0 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]

ABCD1 Gene-Disease associations (from GenCC):

• adrenoleukodystrophy

  Inheritance: XL Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, G2P
• X-linked cerebral adrenoleukodystrophy

  Inheritance: XL Classification: DEFINITIVE, SUPPORTIVE Submitted by: Laboratory for Molecular Medicine, Orphanet
• hereditary spastic paraplegia

  Inheritance: XL Classification: STRONG Submitted by: Genomics England PanelApp
• Hirschsprung disease

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• adrenomyeloneuropathy

  Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant X-153729216-C-T is Benign according to our data. Variant chrX-153729216-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 92329.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 = 0.0081 (913/112729) while in subpopulation NFE AF = 0.0131 (698/53238). AF 95% confidence interval is 0.0123. There are 5 homozygotes in GnomAd4. There are 252 alleles in the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check.
• BS2: High AC in GnomAd4 at 913 XL,AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001440747.1. 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.901-16C>T		intron	N/A	NP_000024.2
	ABCD1	NM_001440747.1		c.901-16C>T		intron	N/A	NP_001427676.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ABCD1	ENST00000218104.6	TSL:1 MANE Select	c.901-16C>T		intron	N/A	ENSP00000218104.3
	ABCD1	ENST00000862307.1		c.901-16C>T		intron	N/A	ENSP00000532366.1
	ABCD1	ENST00000862306.1		c.901-16C>T		intron	N/A	ENSP00000532365.1

Frequencies

GnomAD3 genomes AF: 0.00809 AC: 912 AN: 112675 Hom.: 5 Cov.: 23

Gnomad AFR AF: 0.00171

Gnomad AMI AF: 0.0501

Gnomad AMR AF: 0.00317

Gnomad ASJ AF: 0.00714

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000361

Gnomad FIN AF: 0.00995

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0131

Gnomad OTH AF: 0.00790

GnomAD2 exomes AF: 0.00765 AC: 1395 AN: 182246 AF XY: 0.00734

Gnomad AFR exome AF: 0.00190

Gnomad AMR exome AF: 0.00201

Gnomad ASJ exome AF: 0.00589

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0106

Gnomad NFE exome AF: 0.0131

Gnomad OTH exome AF: 0.00687

GnomAD4 exome AF: 0.0115 AC: 12676 AN: 1097627 Hom.: 82 Cov.: 31 AF XY: 0.0112 AC XY: 4070 AN XY: 363051

African (AFR) AF: 0.00189 AC: 50 AN: 26394

American (AMR) AF: 0.00233 AC: 82 AN: 35203

Ashkenazi Jewish (ASJ) AF: 0.00738 AC: 143 AN: 19384

East Asian (EAS) AF: 0.0000331 AC: 1 AN: 30203

South Asian (SAS) AF: 0.000702 AC: 38 AN: 54128

European-Finnish (FIN) AF: 0.0111 AC: 446 AN: 40284

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4129

European-Non Finnish (NFE) AF: 0.0137 AC: 11501 AN: 841816

Other (OTH) AF: 0.00900 AC: 415 AN: 46086

GnomAD4 genome AF: 0.00810 AC: 913 AN: 112729 Hom.: 5 Cov.: 23 AF XY: 0.00723 AC XY: 252 AN XY: 34865

African (AFR) AF: 0.00170 AC: 53 AN: 31091

American (AMR) AF: 0.00317 AC: 34 AN: 10740

Ashkenazi Jewish (ASJ) AF: 0.00714 AC: 19 AN: 2660

East Asian (EAS) AF: 0.00 AC: 0 AN: 3576

South Asian (SAS) AF: 0.000362 AC: 1 AN: 2759

European-Finnish (FIN) AF: 0.00995 AC: 62 AN: 6229

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

European-Non Finnish (NFE) AF: 0.0131 AC: 698 AN: 53238

Other (OTH) AF: 0.00780 AC: 12 AN: 1538

Alfa AF: 0.0102 Hom.: 81

Bravo AF: 0.00741

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Adrenoleukodystrophy (3)
-	-	3	not specified (3)
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	4.8
DANN	Benign	0.74
PhyloP100		0.011
Mutation Taster		=100/0	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: rs41302176; hg19: chrX-152994671;