Genetic Variant ABCD1:p.Asn509Ser (chrX-153740129-A-G) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 7P and 4B. PM1PP3_StrongPP5BS2

The NM_000033.4(ABCD1):c.1526A>G(p.Asn509Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000661 in 1,209,600 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a pathogenic 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. N509K) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000018 ( 0 hom., 0 hem., cov: 24)

Exomes 𝑓: 0.0000055 ( 0 hom. 1 hem. )

Consequence

ABCD1
NM_000033.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 9.32

Publications

3 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:

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ACMG classification

Classification was made for transcript

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

PM1

In a hotspot region, there are 18 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 11 uncertain in NM_000033.4

PP3

MetaRNN computational evidence supports a deleterious effect, 0.982

PP5

Variant X-153740129-A-G is Pathogenic according to our data. Variant chrX-153740129-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 458633.

BS2

High AC in GnomAdExome4 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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
ABCD1	NM_000033.4	MANE Select	c.1526A>G	p.Asn509Ser	missense	Exon 6 of 10	NP_000024.2
ABCD1	NM_001440747.1		c.1826A>G	p.Asn609Ser	missense	Exon 7 of 11	NP_001427676.1
PLXNB3-AS1	NR_199693.1		n.90-1551T>C		intron	N/A

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ABCD1	ENST00000218104.6	TSL:1 MANE Select	c.1526A>G	p.Asn509Ser	missense	Exon 6 of 10	ENSP00000218104.3	P33897
ABCD1	ENST00000862307.1		c.1826A>G	p.Asn609Ser	missense	Exon 7 of 11	ENSP00000532366.1
ABCD1	ENST00000862306.1		c.1796A>G	p.Asn599Ser	missense	Exon 7 of 11	ENSP00000532365.1

Frequencies

GnomAD3 genomes

AF:

0.0000177

AC:

AN:

112737

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000644

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000549

AC:

AN:

182301

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000367

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000547

AC:

AN:

1096863

Hom.:

Cov.:

AF XY:

0.00000276

AC XY:

AN XY:

362357

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26387

American (AMR)

AF:

0.0000285

AC:

AN:

35130

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19344

East Asian (EAS)

AF:

0.00

AC:

AN:

30172

South Asian (SAS)

AF:

0.00

AC:

AN:

54022

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40410

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4133

European-Non Finnish (NFE)

AF:

0.00000594

AC:

AN:

841246

Other (OTH)

AF:

0.00

AC:

AN:

46019

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.445

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000177

AC:

AN:

112737

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

34919

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.0000644

AC:

AN:

31056

American (AMR)

AF:

0.00

AC:

AN:

10758

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2654

East Asian (EAS)

AF:

0.00

AC:

AN:

3586

South Asian (SAS)

AF:

0.00

AC:

AN:

2767

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6260

Middle Eastern (MID)

AF:

0.00

AC:

AN:

237

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

53218

Other (OTH)

AF:

0.00

AC:

AN:

1519

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.00000000770867), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.400

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ExAC

AF:

0.00000824

AC:

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Adrenoleukodystrophy (3)

not provided (2)

Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.57

BayesDel_addAF

Uncertain

0.072

BayesDel_noAF

Uncertain

-0.020

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.94

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

0.99

M_CAP

Pathogenic

0.54

MetaRNN

Pathogenic

0.98

MetaSVM

Pathogenic

0.80

MutationAssessor

Benign

0.28

PhyloP100

9.3

PrimateAI

Uncertain

0.57

PROVEAN

Pathogenic

-4.5

REVEL

Pathogenic

0.79

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.0060

Polyphen

1.0

Vest4

0.84

MutPred

0.87

Gain of glycosylation at N509 (P = 0.0493)

MVP

1.0

MPC

1.3

ClinPred

0.98

GERP RS

4.8

Varity_R

0.82

gMVP

0.91

Mutation Taster

=33/67

disease causing

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over