X-153725307-C-G

Variant names:

• chrX-153725307-C-G
• rs782161942
• NM_000033.4:c.41C>G

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001440747.1(ABCD1):​c.41C>G​(p.Thr14Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000619 in 1,148,054 control chromosomes in the GnomAD database, including 1 homozygotes. There are 200 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. T14A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00044 (1 hom., 7 hem., cov: 25)
  • Exomes 𝑓: 0.00064 (0 hom. 193 hem.)
• Consequence: ABCD1 NM_001440747.1 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:8
• Conservation: PhyloP100: 0.462
• 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: XL, AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, PanelApp Australia, G2P, Labcorp Genetics (formerly Invitae), Orphanet

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.019428253).
• BP6: Variant X-153725307-C-G is Benign according to our data. Variant chrX-153725307-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 458643.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000442 (50/113096) while in subpopulation AMR AF = 0.000642 (7/10896). AF 95% confidence interval is 0.000453. There are 1 homozygotes in GnomAd4. There are 7 alleles in the male GnomAd4 subpopulation. Median coverage is 25. This position passed quality control check.
• BS2: High AC in GnomAd4 at 50 XL,AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001440747.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ABCD1	NM_000033.4	MANE Select	c.41C>G	p.Thr14Arg	missense	Exon 1 of 10	NP_000024.2
	ABCD1	NM_001440747.1		c.41C>G	p.Thr14Arg	missense	Exon 1 of 11	NP_001427676.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ABCD1	ENST00000218104.6	TSL:1 MANE Select	c.41C>G	p.Thr14Arg	missense	Exon 1 of 10	ENSP00000218104.3
	ABCD1	ENST00000862307.1		c.41C>G	p.Thr14Arg	missense	Exon 1 of 11	ENSP00000532366.1
	ABCD1	ENST00000862306.1		c.41C>G	p.Thr14Arg	missense	Exon 1 of 11	ENSP00000532365.1

Frequencies

GnomAD3 genomes AF: 0.000442 AC: 50 AN: 113096 Hom.: 1 Cov.: 25

Gnomad AFR AF: 0.0000961

Gnomad AMI AF: 0.0103

Gnomad AMR AF: 0.000642

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: 0.000620

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000394 AC: 34 AN: 86391 AF XY: 0.000282

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000149

Gnomad NFE exome AF: 0.000974

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000639 AC: 661 AN: 1034958 Hom.: 0 Cov.: 32 AF XY: 0.000579 AC XY: 193 AN XY: 333206

African (AFR) AF: 0.0000412 AC: 1 AN: 24247

American (AMR) AF: 0.000151 AC: 4 AN: 26478

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 26739

South Asian (SAS) AF: 0.00 AC: 0 AN: 48408

European-Finnish (FIN) AF: 0.000316 AC: 10 AN: 31600

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3018

European-Non Finnish (NFE) AF: 0.000768 AC: 624 AN: 812799

Other (OTH) AF: 0.000504 AC: 22 AN: 43646

GnomAD4 genome AF: 0.000442 AC: 50 AN: 113096 Hom.: 1 Cov.: 25 AF XY: 0.000199 AC XY: 7 AN XY: 35242

African (AFR) AF: 0.0000961 AC: 3 AN: 31203

American (AMR) AF: 0.000642 AC: 7 AN: 10896

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2651

East Asian (EAS) AF: 0.00 AC: 0 AN: 3560

South Asian (SAS) AF: 0.00 AC: 0 AN: 2835

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6298

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 239

European-Non Finnish (NFE) AF: 0.000620 AC: 33 AN: 53211

Other (OTH) AF: 0.00 AC: 0 AN: 1526

Alfa AF: 0.000437 Hom.: 4

Bravo AF: 0.000487

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.00138 AC: 4

ExAC AF: 0.0000653 AC: 4

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	2	3	Adrenoleukodystrophy (5)
-	1	3	not provided (4)
-	-	1	ABCD1-related disorder (1)
-	-	1	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	13
DANN	Benign	0.96
DEOGEN2	Uncertain	0.43	T
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.72	T
M_CAP	Pathogenic	0.35	D
MetaRNN	Benign	0.019	T
MetaSVM	Benign	-0.45	T
MutationAssessor	Benign	0.55	N
PhyloP100		0.46
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-0.57	N
REVEL	Benign	0.21
Sift	Benign	0.17	T
Sift4G	Benign	0.49	T
Polyphen		0.24	B
Vest4		0.073
MutPred		0.40		Gain of solvent accessibility (P = 0.0055)
MVP		0.87
MPC		0.65
ClinPred		0.025	T
GERP RS		2.2
PromoterAI		0.042	Neutral
Varity_R		0.14
gMVP		0.69
Mutation Taster		=98/2	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: rs782161942; hg19: chrX-152990762;