NM_000033.4:c.258C>T

Variant names:

• chrX-153725524-C-T
• rs200660869
• NM_000033.4:c.258C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_000033.4(ABCD1):​c.258C>T​(p.Val86Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00124 in 1,168,449 control chromosomes in the GnomAD database, including 1 homozygotes. There are 462 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 0.00064 (0 hom., 20 hem., cov: 26)
  • Exomes 𝑓: 0.0013 (1 hom. 442 hem.)
• Consequence: ABCD1 NM_000033.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: -0.525
• 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant X-153725524-C-T is Benign according to our data. Variant chrX-153725524-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 368045.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.525 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000636 (72/113296) while in subpopulation NFE AF = 0.00109 (58/53255). AF 95% confidence interval is 0.000864. There are 0 homozygotes in GnomAd4. There are 20 alleles in the male GnomAd4 subpopulation. Median coverage is 26. This position passed quality control check.
• BS2: High AC in GnomAd4 at 72 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.258C>T	p.Val86Val	synonymous	Exon 1 of 10	NP_000024.2
	ABCD1	NM_001440747.1		c.258C>T	p.Val86Val	synonymous	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.258C>T	p.Val86Val	synonymous	Exon 1 of 10	ENSP00000218104.3	P33897
	ABCD1	ENST00000862307.1		c.258C>T	p.Val86Val	synonymous	Exon 1 of 11	ENSP00000532366.1
	ABCD1	ENST00000862306.1		c.258C>T	p.Val86Val	synonymous	Exon 1 of 11	ENSP00000532365.1

Frequencies

GnomAD3 genomes AF: 0.000636 AC: 72 AN: 113246 Hom.: 0 Cov.: 26

Gnomad AFR AF: 0.000224

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000184

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000357

Gnomad FIN AF: 0.000632

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00109

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000851 AC: 103 AN: 121082 AF XY: 0.000601

Gnomad AFR exome AF: 0.000228

Gnomad AMR exome AF: 0.0000907

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00125

Gnomad NFE exome AF: 0.00157

Gnomad OTH exome AF: 0.00157

GnomAD4 exome AF: 0.00131 AC: 1377 AN: 1055153 Hom.: 1 Cov.: 32 AF XY: 0.00131 AC XY: 442 AN XY: 336151

African (AFR) AF: 0.000275 AC: 7 AN: 25482

American (AMR) AF: 0.0000321 AC: 1 AN: 31190

Ashkenazi Jewish (ASJ) AF: 0.0000573 AC: 1 AN: 17445

East Asian (EAS) AF: 0.00 AC: 0 AN: 28872

South Asian (SAS) AF: 0.0000619 AC: 3 AN: 48495

European-Finnish (FIN) AF: 0.00118 AC: 42 AN: 35594

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3300

European-Non Finnish (NFE) AF: 0.00154 AC: 1261 AN: 820512

Other (OTH) AF: 0.00140 AC: 62 AN: 44263

GnomAD4 genome AF: 0.000636 AC: 72 AN: 113296 Hom.: 0 Cov.: 26 AF XY: 0.000564 AC XY: 20 AN XY: 35458

African (AFR) AF: 0.000223 AC: 7 AN: 31354

American (AMR) AF: 0.000184 AC: 2 AN: 10897

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2656

East Asian (EAS) AF: 0.00 AC: 0 AN: 3575

South Asian (SAS) AF: 0.000358 AC: 1 AN: 2792

European-Finnish (FIN) AF: 0.000632 AC: 4 AN: 6327

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 217

European-Non Finnish (NFE) AF: 0.00109 AC: 58 AN: 53255

Other (OTH) AF: 0.00 AC: 0 AN: 1542

Alfa AF: 0.000728 Hom.: 5

Bravo AF: 0.000710

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	Adrenoleukodystrophy (4)
-	-	4	not provided (4)
-	-	3	not specified (3)
-	-	1	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	6.2
DANN	Benign	0.93
PhyloP100		-0.53
PromoterAI		-0.010	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	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

Other links and lift over

dbSNP: rs200660869; hg19: chrX-152990979;