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rs713993050

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PVS1PM2_SupportingPP5_Very_Strong

The NM_000033(ABCD1):c.253dup(p.Arg85ProfsTer110) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD Genomes project. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. F83F) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 25)

Consequence

ABCD1
NM_000033 frameshift

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:3

Conservation

PhyloP100: 1.13

Links

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 17 ACMG points.

PVS1
?
Loss of function variant, product does not undergo nonsense mediated mRNA decay. There are 342 pathogenic variants in the truncated region.
PM2
?
Very rare variant; Number of alleles below threshold, Median coverage is 25.
PP5
?
Variant X:153725514-T>TC is Pathogenic according to our data. Variant chrX-153725514-T-TC is described in ClinVar as [Pathogenic]. Clinvar id is 162148. Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
ABCD1NM_000033.4 linkuse as main transcriptc.253dup p.Arg85ProfsTer110 frameshift_variant 1/10 ENST00000218104.6
ABCD1XM_047441916.1 linkuse as main transcriptc.253dup p.Arg85ProfsTer110 frameshift_variant 1/11
ABCD1XM_047441917.1 linkuse as main transcriptc.253dup p.Arg85ProfsTer110 frameshift_variant 1/8

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
ABCD1ENST00000218104.6 linkuse as main transcriptc.253dup p.Arg85ProfsTer110 frameshift_variant 1/101 NM_000033.4 P1

Frequencies

GnomAD3 genomes
Cov.:
25

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Adrenoleukodystrophy Pathogenic:2
Pathogenic, criteria provided, single submitterclinical testingInvitaeMay 05, 2022This sequence change creates a premature translational stop signal (p.Arg85Profs*110) in the ABCD1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ABCD1 are known to be pathogenic (PMID: 11748843). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with clinical features of X-linked adrenoleukodystrophy (PMID: 15811009, 27489563). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 162148). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, no assertion criteria providedresearchFaculty of Medicine, Iran University of Medical Sciences (IUMS)Sep 17, 2014Present study is the first to report clinical and genetics characteristics of Iranian X-ALD patients, Lorestan province. It also highlighted the importance of genetic counseling through reliable identification of heterozygous as well as homozygote females in consanguineous communities with subsequent elevated prevalence. Unexpectedly, there exist childhood cerebral ALD, adrenomyeloneuropathy, and addison-only disease phenotypes of ALD in our pedigree with the same variant. X-ALD also occurred significantly more in our studied Iranian pedigree compared to its reported prevalence (Odd Ratio 4249.7500, 95% CI 224.6575 to 80390.7075, p-value< 0.0001). -
not provided Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingEurofins Ntd Llc (ga)Dec 02, 2015- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction

Splicing

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.

Other links and lift over

dbSNP: rs713993050; hg19: chrX-152990969;