NM_000026.4:c.1400C>G

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2PP3_ModeratePP5

The NM_000026.4(ADSL):ā€‹c.1400C>Gā€‹(p.Pro467Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,216 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: not found (cov: 32)
Exomes š‘“: 6.8e-7 ( 0 hom. )

Consequence

ADSL
NM_000026.4 missense

Scores

8
7
4

Clinical Significance

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

Conservation

PhyloP100: 4.08
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 5 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.85
PP5
Variant 22-40366467-C-G is Pathogenic according to our data. Variant chr22-40366467-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 381551.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Likely_pathogenic=1}.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
ADSLNM_000026.4 linkc.1400C>G p.Pro467Arg missense_variant Exon 13 of 13 ENST00000623063.3 NP_000017.1 P30566-1X5D8S6

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
ADSLENST00000623063.3 linkc.1400C>G p.Pro467Arg missense_variant Exon 13 of 13 1 NM_000026.4 ENSP00000485525.1 P30566-1
ENSG00000284431ENST00000639722.1 linkn.*1096C>G non_coding_transcript_exon_variant Exon 12 of 31 5 ENSP00000492828.1 A0A1W2PRX2
ENSG00000284431ENST00000639722.1 linkn.*1096C>G 3_prime_UTR_variant Exon 12 of 31 5 ENSP00000492828.1 A0A1W2PRX2

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD3 exomes
AF:
0.00000398
AC:
1
AN:
251416
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
135880
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:
0.00000879
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
6.84e-7
AC:
1
AN:
1461216
Hom.:
0
Cov.:
30
AF XY:
0.00
AC XY:
0
AN XY:
726970
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
9.00e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:1Uncertain:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Pathogenic:1
Mar 03, 2016
GeneDx
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The P467R variant in the ADSL gene has been reported previously in the presence of a second ADSL missense variant in an individual with Type 1 adenylsuccinate lyase deficiency (Spiegel et al, 2006; Zikanova et al., 2010). The P467R variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The P467R variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. Therefore, we interpret P467R as a likely pathogenic variant, however the possibility it may be a rare benign variant cannot be excluded. -

Adenylosuccinate lyase deficiency Uncertain:1
Aug 24, 2021
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change replaces proline with arginine at codon 467 of the ADSL protein (p.Pro467Arg). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and arginine. This variant is not present in population databases (ExAC no frequency). This missense change has been observed in individual(s) with ADSL deficiency (PMID: 16839792, 20127976). ClinVar contains an entry for this variant (Variation ID: 381551). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). Experimental studies have shown that this missense change affects ADSL function (PMID: 22180458). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.22
BayesDel_addAF
Pathogenic
0.49
D
BayesDel_noAF
Pathogenic
0.46
CADD
Pathogenic
27
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.67
D;.;T;T
Eigen
Pathogenic
0.69
Eigen_PC
Uncertain
0.66
FATHMM_MKL
Uncertain
0.96
D
LIST_S2
Uncertain
0.90
D;D;D;D
M_CAP
Pathogenic
0.36
D
MetaRNN
Pathogenic
0.85
D;D;D;D
MetaSVM
Pathogenic
1.0
D
MutationAssessor
Pathogenic
3.2
M;.;.;.
PrimateAI
Benign
0.43
T
PROVEAN
Benign
-0.49
.;N;.;.
REVEL
Pathogenic
0.86
Sift
Uncertain
0.0060
.;D;.;.
Sift4G
Uncertain
0.0090
D;T;.;D
Polyphen
0.89
P;P;.;.
Vest4
0.56
MutPred
0.69
.;.;.;Gain of solvent accessibility (P = 0.0808);
MVP
0.99
MPC
0.92
ClinPred
0.88
D
GERP RS
4.4
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1
Varity_R
0.84
gMVP
0.88

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.13
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.

Other links and lift over

dbSNP: rs1057521071; hg19: chr22-40762471; API