chrX-153725658-G-T

Variant names:

• chrX-153725658-G-T
• rs367799134
• NM_000033.4:c.392G>T

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.392G>T​(p.Gly131Val) variant causes a missense change. The variant allele was found at a frequency of 0.0000413 in 1,209,243 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 17 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000053 (0 hom., 1 hem., cov: 26)
  • Exomes 𝑓: 0.000040 (0 hom. 16 hem.)
• Consequence: ABCD1 NM_000033.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: 4.46
• 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=0.1456699).
• BP6: Variant X-153725658-G-T is Benign according to our data. Variant chrX-153725658-G-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 383794.
• BS2: High AC in GnomAd4 at 6 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.392G>T	p.Gly131Val	missense	Exon 1 of 10	NP_000024.2
	ABCD1	NM_001440747.1		c.392G>T	p.Gly131Val	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.392G>T	p.Gly131Val	missense	Exon 1 of 10	ENSP00000218104.3	P33897
	ABCD1	ENST00000862307.1		c.392G>T	p.Gly131Val	missense	Exon 1 of 11	ENSP00000532366.1
	ABCD1	ENST00000862306.1		c.392G>T	p.Gly131Val	missense	Exon 1 of 11	ENSP00000532365.1

Frequencies

GnomAD3 genomes AF: 0.0000530 AC: 6 AN: 113308 Hom.: 0 Cov.: 26

Gnomad AFR AF: 0.00

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: 0.000112

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000797 AC: 14 AN: 175576 AF XY: 0.0000954

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000185

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000904

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000401 AC: 44 AN: 1095935 Hom.: 0 Cov.: 32 AF XY: 0.0000442 AC XY: 16 AN XY: 362087

African (AFR) AF: 0.00 AC: 0 AN: 26364

American (AMR) AF: 0.000143 AC: 5 AN: 35079

Ashkenazi Jewish (ASJ) AF: 0.000103 AC: 2 AN: 19343

East Asian (EAS) AF: 0.00 AC: 0 AN: 30134

South Asian (SAS) AF: 0.000148 AC: 8 AN: 53893

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39468

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4131

European-Non Finnish (NFE) AF: 0.0000321 AC: 27 AN: 841550

Other (OTH) AF: 0.0000435 AC: 2 AN: 45973

GnomAD4 genome AF: 0.0000530 AC: 6 AN: 113308 Hom.: 0 Cov.: 26 AF XY: 0.0000282 AC XY: 1 AN XY: 35442

African (AFR) AF: 0.00 AC: 0 AN: 31260

American (AMR) AF: 0.00 AC: 0 AN: 10838

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2657

East Asian (EAS) AF: 0.00 AC: 0 AN: 3606

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6324

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

European-Non Finnish (NFE) AF: 0.000112 AC: 6 AN: 53356

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

Alfa AF: 0.000214 Hom.: 1

Bravo AF: 0.0000416

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000149 AC: 1

ExAC AF: 0.000132 AC: 16

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	2	Adrenoleukodystrophy (3)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.092
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.22
CADD	Benign	17
DANN	Benign	0.84
DEOGEN2	Uncertain	0.66	D
FATHMM_MKL	Benign	0.57	D
LIST_S2	Benign	0.84	T
M_CAP	Uncertain	0.21	D
MetaRNN	Benign	0.15	T
MetaSVM	Uncertain	0.64	D
MutationAssessor	Benign	-1.4	N
PhyloP100		4.5
PrimateAI	Benign	0.45	T
PROVEAN	Benign	2.9	N
REVEL	Uncertain	0.41
Sift	Benign	0.86	T
Sift4G	Benign	0.86	T
Polyphen		0.0	B
Vest4		0.019
MVP		0.56
MPC		0.71
ClinPred		0.033	T
GERP RS		5.4
PromoterAI		-0.021	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.15
gMVP		0.71
Mutation Taster		=96/4	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs367799134; hg19: chrX-152991113;