NM_000033.4:c.696G>T

Variant names:

• chrX-153725962-G-T
• rs147595334
• NM_000033.4:c.696G>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.696G>T​(p.Ala232Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00095 in 1,209,504 control chromosomes in the GnomAD database, including 6 homozygotes. There are 315 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. A232A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0038 (3 hom., 109 hem., cov: 26)
  • Exomes 𝑓: 0.00065 (3 hom. 206 hem.)
• Consequence: ABCD1 NM_000033.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -5.48
• 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant X-153725962-G-T is Benign according to our data. Variant chrX-153725962-G-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 368046.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-5.48 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00384 (437/113738) while in subpopulation AFR AF = 0.0124 (389/31417). AF 95% confidence interval is 0.0114. There are 3 homozygotes in GnomAd4. There are 109 alleles in the male GnomAd4 subpopulation. Median coverage is 26. This position passed quality control check.
• BS2: High AC in GnomAd4 at 437 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.696G>T	p.Ala232Ala	synonymous	Exon 1 of 10	NP_000024.2
	ABCD1	NM_001440747.1		c.696G>T	p.Ala232Ala	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.696G>T	p.Ala232Ala	synonymous	Exon 1 of 10	ENSP00000218104.3	P33897
	ABCD1	ENST00000862307.1		c.696G>T	p.Ala232Ala	synonymous	Exon 1 of 11	ENSP00000532366.1
	ABCD1	ENST00000862306.1		c.696G>T	p.Ala232Ala	synonymous	Exon 1 of 11	ENSP00000532365.1

Frequencies

GnomAD3 genomes AF: 0.00384 AC: 436 AN: 113685 Hom.: 3 Cov.: 26

Gnomad AFR AF: 0.0124

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00165

Gnomad ASJ AF: 0.00751

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000131

Gnomad OTH AF: 0.00196

GnomAD2 exomes AF: 0.00153 AC: 275 AN: 179362 AF XY: 0.000990

Gnomad AFR exome AF: 0.0133

Gnomad AMR exome AF: 0.000951

Gnomad ASJ exome AF: 0.00852

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000137

Gnomad OTH exome AF: 0.000894

GnomAD4 exome AF: 0.000650 AC: 712 AN: 1095766 Hom.: 3 Cov.: 32 AF XY: 0.000569 AC XY: 206 AN XY: 362220

African (AFR) AF: 0.0134 AC: 354 AN: 26399

American (AMR) AF: 0.000909 AC: 32 AN: 35203

Ashkenazi Jewish (ASJ) AF: 0.00846 AC: 164 AN: 19376

East Asian (EAS) AF: 0.00 AC: 0 AN: 30200

South Asian (SAS) AF: 0.0000185 AC: 1 AN: 54143

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 38223

Middle Eastern (MID) AF: 0.000725 AC: 3 AN: 4137

European-Non Finnish (NFE) AF: 0.000116 AC: 98 AN: 842013

Other (OTH) AF: 0.00130 AC: 60 AN: 46072

GnomAD4 genome AF: 0.00384 AC: 437 AN: 113738 Hom.: 3 Cov.: 26 AF XY: 0.00304 AC XY: 109 AN XY: 35872

African (AFR) AF: 0.0124 AC: 389 AN: 31417

American (AMR) AF: 0.00165 AC: 18 AN: 10906

Ashkenazi Jewish (ASJ) AF: 0.00751 AC: 20 AN: 2662

East Asian (EAS) AF: 0.00 AC: 0 AN: 3598

South Asian (SAS) AF: 0.00 AC: 0 AN: 2857

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6406

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

European-Non Finnish (NFE) AF: 0.000131 AC: 7 AN: 53436

Other (OTH) AF: 0.00194 AC: 3 AN: 1547

Alfa AF: 0.00148 Hom.: 6

Bravo AF: 0.00426

EpiCase AF: 0.000382

EpiControl AF: 0.000119

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Adrenoleukodystrophy (3)
-	-	2	not specified (2)
-	-	1	Inborn genetic diseases (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.037
DANN	Benign	0.83
PhyloP100		-5.5
PromoterAI		-0.0026	Neutral
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: rs147595334; hg19: chrX-152991417;