rs150151955

Variant names:

• chrX-153726023-C-G
• rs150151955
• NM_000033.4:c.757C>G

Your query was ambiguous. Multiple possible variants found:

• chrX-153726023-C-G
• chrX-153726023-C-T

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.757C>G​(p.Leu253Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00119 in 1,204,688 control chromosomes in the GnomAD database, including 1 homozygotes. There are 461 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L253F) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00061 (0 hom., 18 hem., cov: 26)
  • Exomes 𝑓: 0.0013 (1 hom. 443 hem.)
• Consequence: ABCD1 NM_000033.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:14
• Conservation: PhyloP100: 1.23
• Publications: 3 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 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 11 uncertain in NM_000033.4
• BP4: Computational evidence support a benign effect (MetaRNN=0.044420302).
• BP6: Variant X-153726023-C-G is Benign according to our data. Variant chrX-153726023-C-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 377034.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000614 (70/113974) while in subpopulation NFE AF = 0.00103 (55/53468). AF 95% confidence interval is 0.000811. There are 0 homozygotes in GnomAd4. There are 18 alleles in the male GnomAd4 subpopulation. Median coverage is 26. This position passed quality control check.
• BS2: High AC in GnomAd4 at 70 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.757C>G	p.Leu253Val	missense	Exon 1 of 10	NP_000024.2
	ABCD1	NM_001440747.1		c.757C>G	p.Leu253Val	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.757C>G	p.Leu253Val	missense	Exon 1 of 10	ENSP00000218104.3	P33897
	ABCD1	ENST00000862307.1		c.757C>G	p.Leu253Val	missense	Exon 1 of 11	ENSP00000532366.1
	ABCD1	ENST00000862306.1		c.757C>G	p.Leu253Val	missense	Exon 1 of 11	ENSP00000532365.1

Frequencies

GnomAD3 genomes AF: 0.000614 AC: 70 AN: 113921 Hom.: 0 Cov.: 26

Gnomad AFR AF: 0.000254

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000183

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000347

Gnomad FIN AF: 0.000622

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00103

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000829 AC: 143 AN: 172513 AF XY: 0.000598

Gnomad AFR exome AF: 0.000241

Gnomad AMR exome AF: 0.0000750

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00126

Gnomad NFE exome AF: 0.00145

Gnomad OTH exome AF: 0.00164

GnomAD4 exome AF: 0.00126 AC: 1369 AN: 1090714 Hom.: 1 Cov.: 32 AF XY: 0.00124 AC XY: 443 AN XY: 357750

African (AFR) AF: 0.000267 AC: 7 AN: 26247

American (AMR) AF: 0.0000287 AC: 1 AN: 34788

Ashkenazi Jewish (ASJ) AF: 0.0000526 AC: 1 AN: 19029

East Asian (EAS) AF: 0.00 AC: 0 AN: 30018

South Asian (SAS) AF: 0.0000561 AC: 3 AN: 53496

European-Finnish (FIN) AF: 0.00117 AC: 46 AN: 39198

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4112

European-Non Finnish (NFE) AF: 0.00150 AC: 1253 AN: 838072

Other (OTH) AF: 0.00127 AC: 58 AN: 45754

GnomAD4 genome AF: 0.000614 AC: 70 AN: 113974 Hom.: 0 Cov.: 26 AF XY: 0.000499 AC XY: 18 AN XY: 36104

African (AFR) AF: 0.000254 AC: 8 AN: 31537

American (AMR) AF: 0.000183 AC: 2 AN: 10921

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2661

East Asian (EAS) AF: 0.00 AC: 0 AN: 3616

South Asian (SAS) AF: 0.000348 AC: 1 AN: 2875

European-Finnish (FIN) AF: 0.000622 AC: 4 AN: 6435

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

European-Non Finnish (NFE) AF: 0.00103 AC: 55 AN: 53468

Other (OTH) AF: 0.00 AC: 0 AN: 1556

Alfa AF: 0.00118 Hom.: 22

Bravo AF: 0.000680

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.00173 AC: 5

ESP6500AA AF: 0.000262 AC: 1

ESP6500EA AF: 0.00149 AC: 10

ExAC AF: 0.00112 AC: 136

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	7	not provided (7)
-	-	4	Adrenoleukodystrophy (4)
-	-	2	not specified (2)
-	-	1	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.020	T
BayesDel_noAF	Pathogenic	0.18
CADD	Benign	17
DANN	Benign	0.97
DEOGEN2	Uncertain	0.77	D
FATHMM_MKL	Benign	0.48	N
LIST_S2	Benign	0.79	T
M_CAP	Pathogenic	0.38	D
MetaRNN	Benign	0.044	T
MetaSVM	Uncertain	0.15	D
MutationAssessor	Benign	0.53	N
PhyloP100		1.2
PrimateAI	Uncertain	0.75	T
PROVEAN	Benign	-0.97	N
REVEL	Uncertain	0.61
Sift	Benign	0.19	T
Sift4G	Benign	0.15	T
Polyphen		0.37	B
Vest4		0.33
MVP		1.0
MPC		0.63
ClinPred		0.014	T
GERP RS		5.4
PromoterAI		0.14	Neutral
Varity_R		0.26
gMVP		0.83
Mutation Taster		=77/23	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: rs150151955; hg19: chrX-152991478;