NM_000033.4:c.12C>G

Variant names:

• chrX-153725278-C-G
• NM_000033.4:c.12C>G

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_Strong BP6_Moderate BP7 BS2

The NM_000033.4(ABCD1):​c.12C>G​(p.Leu4Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000292 in 1,027,345 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 2 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Synonymous variant affecting the same amino acid position (i.e. L4L) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 25)
  • Exomes 𝑓: 0.0000029 (0 hom. 2 hem.)
• Consequence: ABCD1 NM_000033.4 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.408
• 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 -11 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.63).
• BP6: Variant X-153725278-C-G is Benign according to our data. Variant chrX-153725278-C-G is described in ClinVar as Likely_benign. ClinVar VariationId is 1100417.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-0.408 with no splicing effect.
• BS2: High Hemizygotes in GnomAdExome4 at 2 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.12C>G	p.Leu4Leu	synonymous	Exon 1 of 10	NP_000024.2
	ABCD1	NM_001440747.1		c.12C>G	p.Leu4Leu	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.12C>G	p.Leu4Leu	synonymous	Exon 1 of 10	ENSP00000218104.3	P33897
	ABCD1	ENST00000862307.1		c.12C>G	p.Leu4Leu	synonymous	Exon 1 of 11	ENSP00000532366.1
	ABCD1	ENST00000862306.1		c.12C>G	p.Leu4Leu	synonymous	Exon 1 of 11	ENSP00000532365.1

Frequencies

GnomAD3 genomes Cov.: 25

GnomAD4 exome AF: 0.00000292 AC: 3 AN: 1027345 Hom.: 0 Cov.: 32 AF XY: 0.00000607 AC XY: 2 AN XY: 329295

African (AFR) AF: 0.00 AC: 0 AN: 23945

American (AMR) AF: 0.00 AC: 0 AN: 25751

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 17650

East Asian (EAS) AF: 0.00 AC: 0 AN: 26550

South Asian (SAS) AF: 0.00 AC: 0 AN: 47577

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 29947

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2906

European-Non Finnish (NFE) AF: 0.00000371 AC: 3 AN: 809670

Other (OTH) AF: 0.00 AC: 0 AN: 43349

GnomAD4 genome Cov.: 25

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Adrenoleukodystrophy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.63
CADD	Benign	3.9
DANN	Benign	0.77
PhyloP100		-0.41
PromoterAI		-0.033	Neutral

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

hg19: chrX-152990733;