dbSNP rs201774661: ABCD1:p.Ser606Pro (chrX-153743022-T-C) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 7P and 4B. PM1PM2PM5PP3BP4_Strong

The NM_000033.4(ABCD1):c.1816T>C(p.Ser606Pro) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts 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. S606L) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 25)

Consequence

ABCD1
NM_000033.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:3B:4

Conservation

PhyloP100: 5.17

Publications

25 publications found

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:

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

PLXNB3-AS1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM1

In a hotspot region, there are 9 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 benign, 3 uncertain in NM_000033.4

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chrX-153743023-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 11310.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

PP3

Multiple lines of computational evidence support a deleterious effect 6: AlphaMissense, BayesDel_addAF, BayesDel_noAF, MutationAssessor, REVEL, REVEL [when max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]

BP4

Computational evidence support a benign effect (MetaRNN=0.019254386).

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
ABCD1	NM_000033.4	MANE Select	c.1816T>C	p.Ser606Pro	missense	Exon 8 of 10	NP_000024.2
ABCD1	NM_001440747.1		c.2116T>C	p.Ser706Pro	missense	Exon 9 of 11	NP_001427676.1
PLXNB3-AS1	NR_199693.1		n.90-4444A>G		intron	N/A

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ABCD1	ENST00000218104.6	TSL:1 MANE Select	c.1816T>C	p.Ser606Pro	missense	Exon 8 of 10	ENSP00000218104.3	P33897
ABCD1	ENST00000862307.1		c.2116T>C	p.Ser706Pro	missense	Exon 9 of 11	ENSP00000532366.1
ABCD1	ENST00000862306.1		c.2086T>C	p.Ser696Pro	missense	Exon 9 of 11	ENSP00000532365.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.000381

AC:

AN:

149800

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.000772

Gnomad AMR exome

AF:

0.000333

Gnomad ASJ exome

AF:

0.000454

Gnomad EAS exome

AF:

0.000419

Gnomad FIN exome

AF:

0.000217

Gnomad NFE exome

AF:

0.000423

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

Alfa

AF:

0.0402

Hom.:

ExAC

AF:

0.00785

AC:

945

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Adrenoleukodystrophy (6)

not specified (1)

X-linked cerebral adrenoleukodystrophy (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.98

BayesDel_addAF

Pathogenic

0.67

BayesDel_noAF

Pathogenic

0.72

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.99

FATHMM_MKL

Uncertain

0.95

LIST_S2

Pathogenic

1.0

MetaRNN

Benign

0.019

MetaSVM

Pathogenic

0.91

MutationAssessor

Pathogenic

3.4

PhyloP100

5.2

PrimateAI

Uncertain

0.57

PROVEAN

Uncertain

-4.0

REVEL

Pathogenic

0.88

Sift

Uncertain

0.0010

Sift4G

Uncertain

0.0020

Polyphen

0.98

Vest4

0.26

MVP

1.0

MPC

1.7

ClinPred

0.078

GERP RS

5.5

Varity_R

0.97

gMVP

1.0

Mutation Taster

=3/97

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

Splicevardb

2.0

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over