22-40359279-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2PP5BP4

The NM_000026.4(ADSL):​c.674T>C​(p.Met225Thr) 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 Pathogenic (no stars).

Frequency

Genomes: not found (cov: 32)

Consequence

ADSL
NM_000026.4 missense

Scores

2
4
13

Clinical Significance

Pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 4.26
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]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 22-40359279-T-C is Pathogenic according to our data. Variant chr22-40359279-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 2468.Status of the report is no_assertion_criteria_provided, 0 stars.
BP4
Computational evidence support a benign effect (MetaRNN=0.40242743). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
ADSLNM_000026.4 linkuse as main transcriptc.674T>C p.Met225Thr missense_variant 6/13 ENST00000623063.3

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
ADSLENST00000623063.3 linkuse as main transcriptc.674T>C p.Met225Thr missense_variant 6/131 NM_000026.4 P1P30566-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
31
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: no assertion criteria provided
LINK: link

Submissions by phenotype

Adenylosuccinate lyase deficiency Pathogenic:1
Pathogenic, no assertion criteria providedliterature onlyOMIMJan 01, 2009- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.23
BayesDel_addAF
Pathogenic
0.19
D
BayesDel_noAF
Uncertain
0.040
CADD
Benign
23
DANN
Benign
0.95
DEOGEN2
Benign
0.076
T;D;.;T;T;T;T;.
Eigen
Benign
0.010
Eigen_PC
Benign
0.21
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Benign
0.84
T;T;T;T;T;T;T;T
M_CAP
Benign
0.037
D
MetaRNN
Benign
0.40
T;T;T;T;T;T;T;T
MetaSVM
Benign
-0.56
T
MutationAssessor
Benign
1.7
.;L;L;.;.;.;.;.
MutationTaster
Benign
1.0
A;A;A
PrimateAI
Uncertain
0.64
T
PROVEAN
Uncertain
-2.4
.;.;N;.;.;.;.;.
REVEL
Uncertain
0.41
Sift
Benign
0.065
.;.;T;.;.;.;.;.
Sift4G
Benign
0.20
T;T;T;.;T;T;.;.
Polyphen
0.0080, 0.0030
.;B;B;.;.;.;.;.
Vest4
0.54, 0.68, 0.79
MutPred
0.44
.;.;.;.;Loss of stability (P = 0.0141);.;.;.;
MVP
0.81
MPC
0.83
ClinPred
0.82
D
GERP RS
5.0
RBP_binding_hub_radar
0.92
RBP_regulation_power_radar
2.6
Varity_R
0.55
gMVP
0.81

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.030
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: rs119450945; hg19: chr22-40755283; API