chrX-153725306-A-G

Variant names:

• chrX-153725306-A-G
• rs781900720
• NM_000033.4:c.40A>G

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_Moderate BP6 BS2

The NM_000033.4(ABCD1):​c.40A>G​(p.Thr14Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000497 in 1,147,099 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 22 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T14R) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000027 (0 hom., 1 hem., cov: 25)
  • Exomes 𝑓: 0.000052 (0 hom. 21 hem.)
• Consequence: ABCD1 NM_000033.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:6
• Conservation: PhyloP100: 0.522
• 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 -7 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.088257074).
• BP6: Variant X-153725306-A-G is Benign according to our data. Variant chrX-153725306-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 434063.
• BS2: High AC in GnomAdExome4 at 54 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.40A>G	p.Thr14Ala	missense	Exon 1 of 10	NP_000024.2
	ABCD1	NM_001440747.1		c.40A>G	p.Thr14Ala	missense	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.40A>G	p.Thr14Ala	missense	Exon 1 of 10	ENSP00000218104.3	P33897
	ABCD1	ENST00000862307.1		c.40A>G	p.Thr14Ala	missense	Exon 1 of 11	ENSP00000532366.1
	ABCD1	ENST00000862306.1		c.40A>G	p.Thr14Ala	missense	Exon 1 of 11	ENSP00000532365.1

Frequencies

GnomAD3 genomes AF: 0.0000266 AC: 3 AN: 112902 Hom.: 0 Cov.: 25

Gnomad AFR AF: 0.0000321

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00131

GnomAD2 exomes AF: 0.0000812 AC: 7 AN: 86193 AF XY: 0.0000405

Gnomad AFR exome AF: 0.000212

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000158

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000522 AC: 54 AN: 1034197 Hom.: 0 Cov.: 32 AF XY: 0.0000631 AC XY: 21 AN XY: 332611

African (AFR) AF: 0.00 AC: 0 AN: 24197

American (AMR) AF: 0.00 AC: 0 AN: 26379

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18023

East Asian (EAS) AF: 0.0000750 AC: 2 AN: 26662

South Asian (SAS) AF: 0.000124 AC: 6 AN: 48380

European-Finnish (FIN) AF: 0.0000316 AC: 1 AN: 31623

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3012

European-Non Finnish (NFE) AF: 0.0000443 AC: 36 AN: 812327

Other (OTH) AF: 0.000206 AC: 9 AN: 43594

GnomAD4 genome AF: 0.0000266 AC: 3 AN: 112902 Hom.: 0 Cov.: 25 AF XY: 0.0000285 AC XY: 1 AN XY: 35080

African (AFR) AF: 0.0000321 AC: 1 AN: 31155

American (AMR) AF: 0.00 AC: 0 AN: 10890

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2650

East Asian (EAS) AF: 0.00 AC: 0 AN: 3550

South Asian (SAS) AF: 0.00 AC: 0 AN: 2821

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6275

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 240

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 53113

Other (OTH) AF: 0.00131 AC: 2 AN: 1530

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000491

ExAC AF: 0.0000812 AC: 5

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.061
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	13
DANN	Benign	0.81
DEOGEN2	Benign	0.36	T
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.56	T
M_CAP	Pathogenic	0.30	D
MetaRNN	Benign	0.088	T
MetaSVM	Benign	-0.35	T
MutationAssessor	Benign	0.55	N
PhyloP100		0.52
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-0.34	N
REVEL	Benign	0.19
Sift	Benign	0.23	T
Sift4G	Benign	0.62	T
Polyphen		0.0	B
Vest4		0.014
MutPred		0.25		Loss of phosphorylation at T14 (P = 0.0168)
MVP		0.88
MPC		0.55
ClinPred		0.032	T
GERP RS		3.9
PromoterAI		0.021	Neutral
Varity_R		0.081
gMVP		0.46
Mutation Taster		=94/6	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: rs781900720; hg19: chrX-152990761;