chrX-153725867-G-A

Variant names:

• chrX-153725867-G-A
• rs139415350
• NM_000033.4:c.601G>A

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000033.4(ABCD1):​c.601G>A​(p.Val201Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000108 in 1,210,757 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 29 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. V201V) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00048 (0 hom., 9 hem., cov: 26)
  • Exomes 𝑓: 0.000070 (0 hom. 20 hem.)
• Consequence: ABCD1 NM_000033.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.454
• 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 -18 ACMG points.

• PM1: In a hotspot region, there are 8 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 10 uncertain in NM_000033.4
• BP4: Computational evidence support a benign effect (MetaRNN=0.056189775).
• BP6: Variant X-153725867-G-A is Benign according to our data. Variant chrX-153725867-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 585357.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000476 (54/113553) while in subpopulation AFR AF = 0.00137 (43/31387). AF 95% confidence interval is 0.00104. There are 0 homozygotes in GnomAd4. There are 9 alleles in the male GnomAd4 subpopulation. Median coverage is 26. This position passed quality control check.
• BS2: High AC in GnomAd4 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.601G>A	p.Val201Met	missense	Exon 1 of 10	NP_000024.2
	ABCD1	NM_001440747.1		c.601G>A	p.Val201Met	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.601G>A	p.Val201Met	missense	Exon 1 of 10	ENSP00000218104.3	P33897
	BCAP31	ENST00000862067.1		c.-186C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 8	ENSP00000532126.1
	BCAP31	ENST00000968754.1		c.-186C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 8	ENSP00000638813.1

Frequencies

GnomAD3 genomes AF: 0.000476 AC: 54 AN: 113500 Hom.: 0 Cov.: 26

Gnomad AFR AF: 0.00137

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000920

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: 0.0000187

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000148 AC: 27 AN: 181930 AF XY: 0.000149

Gnomad AFR exome AF: 0.00168

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: 0.0000370

Gnomad OTH exome AF: 0.000443

GnomAD4 exome AF: 0.0000702 AC: 77 AN: 1097204 Hom.: 0 Cov.: 32 AF XY: 0.0000551 AC XY: 20 AN XY: 362994

African (AFR) AF: 0.00193 AC: 51 AN: 26403

American (AMR) AF: 0.0000284 AC: 1 AN: 35205

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19384

East Asian (EAS) AF: 0.00 AC: 0 AN: 30204

South Asian (SAS) AF: 0.00 AC: 0 AN: 54144

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39534

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4136

European-Non Finnish (NFE) AF: 0.0000119 AC: 10 AN: 842109

Other (OTH) AF: 0.000325 AC: 15 AN: 46085

GnomAD4 genome AF: 0.000476 AC: 54 AN: 113553 Hom.: 0 Cov.: 26 AF XY: 0.000252 AC XY: 9 AN XY: 35699

African (AFR) AF: 0.00137 AC: 43 AN: 31387

American (AMR) AF: 0.000919 AC: 10 AN: 10879

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2662

East Asian (EAS) AF: 0.00 AC: 0 AN: 3593

South Asian (SAS) AF: 0.00 AC: 0 AN: 2819

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6356

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 218

European-Non Finnish (NFE) AF: 0.0000187 AC: 1 AN: 53401

Other (OTH) AF: 0.00 AC: 0 AN: 1549

Alfa AF: 0.000141 Hom.: 1

Bravo AF: 0.000480

ESP6500AA AF: 0.00156 AC: 6

ESP6500EA AF: 0.000149 AC: 1

ExAC AF: 0.000165 AC: 20

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.090
CADD	Benign	18
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.93	D
FATHMM_MKL	Benign	0.15	N
LIST_S2	Uncertain	0.87	D
M_CAP	Pathogenic	0.62	D
MetaRNN	Benign	0.056	T
MetaSVM	Pathogenic	1.3	D
MutationAssessor	Uncertain	2.7	M
PhyloP100		0.45
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	-1.8	N
REVEL	Uncertain	0.42
Sift	Uncertain	0.011	D
Sift4G	Uncertain	0.0030	D
Polyphen		0.23	B
Vest4		0.099
MVP		0.97
MPC		0.88
ClinPred		0.026	T
GERP RS		1.3
PromoterAI		0.047	Neutral
Varity_R		0.20
gMVP		0.80
Mutation Taster		=88/12	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: rs139415350; hg19: chrX-152991322;