22-40346510-T-C
Variant names:
Variant summary
Our verdict is Likely pathogenic. Variant got 9 ACMG points: 10P and 1B. PM2PP5_Very_StrongBP4
The NM_000026.4(ADSL):c.-49T>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000767 in 1,565,074 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000064 ( 0 hom. )
Consequence
ADSL
NM_000026.4 5_prime_UTR
NM_000026.4 5_prime_UTR
Scores
2
Clinical Significance
Conservation
PhyloP100: -0.0620
Genes affected
ADSL (HGNC:291): (adenylosuccinate lyase) The protein encoded by this gene belongs to the lyase 1 family. It is an essential enzyme involved in purine metabolism, and catalyzes two non-sequential reactions in the de novo purine biosynthetic pathway: the conversion of succinylaminoimidazole carboxamide ribotide (SAICAR) to aminoimidazole carboxamide ribotide (AICAR) and the conversion of adenylosuccinate (S-AMP) to adenosine monophosphate (AMP). Mutations in this gene are associated with adenylosuccinase deficiency (ADSLD), a disorder marked with psychomotor retardation, epilepsy or autistic features. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Dec 2015]
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ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 9 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 22-40346510-T-C is Pathogenic according to our data. Variant chr22-40346510-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 985789.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.41). . Strength limited to SUPPORTING due to the PP5.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
ADSL | ENST00000623063 | c.-49T>C | 5_prime_UTR_variant | Exon 1 of 13 | 1 | NM_000026.4 | ENSP00000485525.1 | |||
ENSG00000284431 | ENST00000639722.1 | n.-49T>C | upstream_gene_variant | 5 | ENSP00000492828.1 |
Frequencies
GnomAD3 genomes AF: 0.0000197 AC: 3AN: 152210Hom.: 0 Cov.: 32
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GnomAD4 exome AF: 0.00000637 AC: 9AN: 1412864Hom.: 0 Cov.: 31 AF XY: 0.00000286 AC XY: 2AN XY: 699550
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GnomAD4 genome AF: 0.0000197 AC: 3AN: 152210Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74368
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Adenylosuccinate lyase deficiency Pathogenic:2
Pathogenic, no assertion criteria provided | literature only | OMIM | Jul 01, 2002 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Mar 20, 2023 | This variant occurs in a non-coding region of the ADSL gene. It does not change the encoded amino acid sequence of the ADSL protein. This variant is present in population databases (no rsID available, gnomAD 0.001%). This variant has been observed in individual(s) with adenylosuccinate lyase deficiency (PMID: 10958654, 12016589, 23937257). ClinVar contains an entry for this variant (Variation ID: 985789). Studies have shown that this variant alters ADSL gene expression (PMID: 12016589, 25910213). For these reasons, this variant has been classified as Pathogenic. - |
Inborn genetic diseases Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Dec 01, 2017 | - - |
Computational scores
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
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Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at