X-153736123-G-A

Position:

chrX-153736123-G-A

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 2P and 8B. PM1BP4_ModerateBP6_ModerateBS2

The NM_000033.4(ABCD1):c.1093G>A(p.Val365Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000152 in 1,120,811 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 9 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict 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. V365E) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0000091 ( 0 hom., 1 hem., cov: 24)

Exomes 𝑓: 0.000016 ( 0 hom. 8 hem. )

Consequence

ABCD1
NM_000033.4 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 1.60

Variant links:

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]

ABCD1 links:

LOC124905226 (HGNC:):

LOC124905226 links:

PLXNB3-AS1 (HGNC:40454): (PLXNB3 antisense RNA 1)

PLXNB3-AS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

PM1

In a domain ABC transmembrane type-1 (size 292) in uniprot entity ABCD1_HUMAN there are 177 pathogenic changes around while only 40 benign (82%) in NM_000033.4

BP4

Computational evidence support a benign effect (MetaRNN=0.24105766).

BP6

Variant X-153736123-G-A is Benign according to our data. Variant chrX-153736123-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 1102382.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High Hemizygotes in GnomAdExome4 at 8 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
ABCD1	NM_000033.4 linkuse as main transcript	c.1093G>A	p.Val365Met	missense_variant	3/10	ENST00000218104.6
LOC124905226	XR_007068350.1 linkuse as main transcript	n.4228C>T		non_coding_transcript_exon_variant	2/2
ABCD1	XM_047441916.1 linkuse as main transcript	c.1093G>A	p.Val365Met	missense_variant	3/11
ABCD1	XM_047441917.1 linkuse as main transcript	c.1093G>A	p.Val365Met	missense_variant	3/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
ABCD1	ENST00000218104.6 linkuse as main transcript	c.1093G>A	p.Val365Met	missense_variant	3/10	1	NM_000033.4	P1
PLXNB3-AS1	ENST00000434284.1 linkuse as main transcript	n.581-164C>T		intron_variant, non_coding_transcript_variant		3
ABCD1	ENST00000443684.2 linkuse as main transcript	n.96G>A		non_coding_transcript_exon_variant	2/6	3

Frequencies

GnomAD3 genomes

AF:

0.00000913

AC:

AN:

109545

Hom.:

Cov.:

AF XY:

0.0000300

AC XY:

AN XY:

33319

show subpopulations

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:

0.0000191

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000274

AC:

AN:

182211

Hom.:

AF XY:

0.0000594

AC XY:

AN XY:

67307

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000618

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000158

AC:

AN:

1011186

Hom.:

Cov.:

AF XY:

0.0000243

AC XY:

AN XY:

329306

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000616

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000425

Gnomad4 SAS exome

AF:

0.0000749

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000889

Gnomad4 OTH exome

AF:

0.0000501

GnomAD4 genome

AF:

0.00000912

AC:

AN:

109625

Hom.:

Cov.:

AF XY:

0.0000300

AC XY:

AN XY:

33387

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000191

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000189

ExAC

AF:

0.0000577

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.000119

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Adrenoleukodystrophy

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 27, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.11

BayesDel_noAF

Benign

-0.21

CADD

Benign

6.3

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.43

FATHMM_MKL

Uncertain

0.84

LIST_S2

Benign

0.65

M_CAP

Uncertain

0.099

MetaRNN

Benign

0.24

MetaSVM

Benign

-0.53

MutationAssessor

Uncertain

2.1

MutationTaster

Benign

0.70

PrimateAI

Benign

0.35

PROVEAN

Benign

-0.84

REVEL

Benign

0.27

Sift

Benign

0.31

Sift4G

Benign

0.26

Polyphen

0.0070

Vest4

0.32

MutPred

0.30

Loss of methylation at K366 (P = 0.0319);

MVP

0.87

MPC

0.57

ClinPred

0.086

GERP RS

-0.23

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.059

gMVP

0.82

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over