NM_000033.4:c.249C>T

Variant names:

• chrX-153725515-C-T
• rs782628755
• NM_000033.4:c.249C>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BS1 BS2

The NM_000033.4(ABCD1):​c.249C>T​(p.Phe83Phe) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000391 in 1,159,202 control chromosomes in the GnomAD database, including 2 homozygotes. There are 154 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).

• Frequency:
  • Genomes: 𝑓 0.00019 (0 hom., 9 hem., cov: 25)
  • Exomes 𝑓: 0.00041 (2 hom. 145 hem.)
• Consequence: ABCD1 NM_000033.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4
• Conservation: PhyloP100: 1.13
• 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]

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.57).
• BP6: Variant X-153725515-C-T is Benign according to our data. Variant chrX-153725515-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 166623.
• BP7: Synonymous conserved (PhyloP=1.13 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. GnomAdExome4 allele frequency = 0.000413 (432/1045999) while in subpopulation SAS AF = 0.000483 (23/47611). AF 95% confidence interval is 0.000409. There are 2 homozygotes in GnomAdExome4. There are 145 alleles in the male GnomAdExome4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 21 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.249C>T	p.Phe83Phe	synonymous	Exon 1 of 10	NP_000024.2
	ABCD1	NM_001440747.1		c.249C>T	p.Phe83Phe	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.249C>T	p.Phe83Phe	synonymous	Exon 1 of 10	ENSP00000218104.3	P33897
	ABCD1	ENST00000862307.1		c.249C>T	p.Phe83Phe	synonymous	Exon 1 of 11	ENSP00000532366.1
	ABCD1	ENST00000862306.1		c.249C>T	p.Phe83Phe	synonymous	Exon 1 of 11	ENSP00000532365.1

Frequencies

GnomAD3 genomes AF: 0.000186 AC: 21 AN: 113152 Hom.: 0 Cov.: 25

Gnomad AFR AF: 0.0000320

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000920

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000357

Gnomad FIN AF: 0.000633

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000263

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000388 AC: 44 AN: 113443 AF XY: 0.000515

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000195

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00109

Gnomad NFE exome AF: 0.000483

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000413 AC: 432 AN: 1045999 Hom.: 2 Cov.: 32 AF XY: 0.000439 AC XY: 145 AN XY: 330657

African (AFR) AF: 0.0000398 AC: 1 AN: 25131

American (AMR) AF: 0.000238 AC: 7 AN: 29391

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 17307

East Asian (EAS) AF: 0.00 AC: 0 AN: 28307

South Asian (SAS) AF: 0.000483 AC: 23 AN: 47611

European-Finnish (FIN) AF: 0.000747 AC: 26 AN: 34814

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3111

European-Non Finnish (NFE) AF: 0.000447 AC: 365 AN: 816466

Other (OTH) AF: 0.000228 AC: 10 AN: 43861

GnomAD4 genome AF: 0.000186 AC: 21 AN: 113203 Hom.: 0 Cov.: 25 AF XY: 0.000254 AC XY: 9 AN XY: 35369

African (AFR) AF: 0.0000319 AC: 1 AN: 31308

American (AMR) AF: 0.0000919 AC: 1 AN: 10880

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 3567

South Asian (SAS) AF: 0.000358 AC: 1 AN: 2797

European-Finnish (FIN) AF: 0.000633 AC: 4 AN: 6316

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

European-Non Finnish (NFE) AF: 0.000263 AC: 14 AN: 53231

Other (OTH) AF: 0.00 AC: 0 AN: 1548

Alfa AF: 0.000217 Hom.: 1

Bravo AF: 0.000155

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	3	Adrenoleukodystrophy (3)
-	1	1	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.57
CADD	Benign	9.3
DANN	Benign	0.93
PhyloP100		1.1
PromoterAI		0.010	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
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: rs782628755; hg19: chrX-152990970; COSMIC: COSV105100759; COSMIC: COSV105100759;