rs374259530

Positions:

chr22-40350018-T-C

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2PP3_ModeratePP5_Very_Strong

The NM_000026.4(ADSL):c.340T>C(p.Tyr114His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000985 in 1,613,908 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

Frequency

Genomes: 𝑓 0.000085 ( 0 hom., cov: 31)

Exomes 𝑓: 0.00010 ( 0 hom. )

Consequence

ADSL
NM_000026.4 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:10

Conservation

PhyloP100: 7.52

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]

ADSL links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.93

PP5

Variant 22-40350018-T-C is Pathogenic according to our data. Variant chr22-40350018-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 204807.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-40350018-T-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ADSL	NM_000026.4 linkuse as main transcript	c.340T>C	p.Tyr114His	missense_variant	2/13	ENST00000623063.3	NP_000017.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ADSL	ENST00000623063.3 linkuse as main transcript	c.340T>C	p.Tyr114His	missense_variant	2/13	1	NM_000026.4	ENSP00000485525	P1	P30566-1

Frequencies

GnomAD3 genomes

AF:

0.0000854

AC:

AN:

152228

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

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:

0.000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000358

AC:

AN:

251242

Hom.:

AF XY:

0.0000516

AC XY:

AN XY:

135786

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:

0.0000793

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000999

AC:

146

AN:

1461680

Hom.:

Cov.:

AF XY:

0.000106

AC XY:

AN XY:

727150

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:

0.000129

Gnomad4 OTH exome

AF:

0.0000497

GnomAD4 genome

AF:

0.0000854

AC:

AN:

152228

Hom.:

Cov.:

AF XY:

0.0000941

AC XY:

AN XY:

74380

show subpopulations

Gnomad4 AFR

AF:

0.0000724

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000176

Hom.:

Bravo

AF:

0.0000756

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000412

AC:

EpiCase

AF:

0.000164

EpiControl

AF:

0.0000593

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Adenylosuccinate lyase deficiency

Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 25, 2024	This sequence change replaces tyrosine, which is neutral and polar, with histidine, which is basic and polar, at codon 114 of the ADSL protein (p.Tyr114His). This variant is present in population databases (rs374259530, gnomAD 0.007%). This missense change has been observed in individual(s) with adenylosuccinate lyase deficiency (PMID: 10888601, 18524658, 20127976). ClinVar contains an entry for this variant (Variation ID: 204807). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt ADSL protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects ADSL function (PMID: 22180458). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jul 16, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 22, 2024	Variant summary: ADSL c.340T>C (p.Tyr114His) results in a conservative amino acid change located in the Fumarate lyase, N-terminal domain (IPR022761) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3.6e-05 in 251242 control chromosomes. c.340T>C has been reported in the literature in individuals affected with Adenylosuccinate Lyase Deficiency (example, Zikanova_2010). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity in vitro (Zikanova_2010). The following publication have been ascertained in the context of this evaluation (PMID: 20127976). ClinVar contains an entry for this variant (Variation ID: 204807). Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 31, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Aug 04, 2021	- -

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jan 24, 2022	Published functional studies demonstrate pronounced protein instability and significantly reduced or absent enzyme activity (Kmoch et al., 2000; Zikanova et al., 2010); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at a significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 20127976, 22812634, 16839792, 10888601, 18524658, 29655203, 31467849, 31623504, 22180458, 31589614, 17188615, 33648541) -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2017	- -

Inborn genetic diseases

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 17, 2021

The c.340T>C (p.Y114H) alteration is located in exon 2 (coding exon 2) of the ADSL gene. This alteration results from a T to C substitution at nucleotide position 340, causing the tyrosine (Y) at amino acid position 114 to be replaced by a histidine (H). Based on data from the Genome Aggregation Database (gnomAD), the ADSL c.340T>C alteration was observed in 0.0035% (10/282644) of total alleles studied, with a frequency of 0.007% (9/128972) in the European (non-Finnish) subpopulation. This alteration has been reported in the compound heterozygous state with another ADSL alteration in several unrelated patients with clinical and biochemical features consistent with adenylosuccinase deficiency (Kmoch, 2000; Mouchegh, 2007; Jurecka, 2008; Mastrangelo, 2019). This amino acid position is well conserved in available vertebrate species. In vitro studies have demonstrated protein instability and significantly reduced or absent ADSL activity for the p.Y114H alteration (Kmoch, 2000; Jurecka, 2008; Zikanova, 2010). The p.Y114H alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. -

ADSL-related disorder

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 03, 2024

The ADSL c.340T>C variant is predicted to result in the amino acid substitution p.Tyr114His. This variant has been reported in the compound heterozygous state in individuals with adenylosuccinate lyase (ADSL) deficiency (Kmoch et al. 2000. PubMed ID: 10888601; Jurecka et al. 2008. PubMed ID: 18524658). The Tyr114 residue is involved in the formation of the catalytic site and in vitro functional studies indicated that the substitution p.Tyr114His results in low residual activity (Zikanova et al. 2010. PubMed ID: 20127976). This variant is reported in 0.0070% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as pathogenic. -

Difficulty standing;C0560046:Inability to walk;C1837397:Severe global developmental delay;C1854838:Progressive neurologic deterioration;C4021759:Generalized myoclonic seizure

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Jun 22, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.95

BayesDel_addAF

Pathogenic

0.44

BayesDel_noAF

Pathogenic

0.58

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.27

T;D;.;T;T;T;.

Eigen

Pathogenic

0.92

Eigen_PC

Pathogenic

0.84

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.98

D;D;D;D;D;D;D

M_CAP

Pathogenic

0.61

MetaRNN

Pathogenic

0.93

D;D;D;D;D;D;D

MetaSVM

Pathogenic

1.0

MutationAssessor

Pathogenic

4.0

.;H;H;.;.;.;.

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Pathogenic

0.88

PROVEAN

Pathogenic

-4.5

.;.;D;.;D;.;.

REVEL

Pathogenic

0.97

Sift

Pathogenic

0.0

.;.;D;.;D;.;.

Sift4G

Pathogenic

0.0

D;D;D;.;D;.;.

Polyphen

1.0, 1.0

.;D;D;.;.;.;.

Vest4

0.87, 0.92, 0.96

MVP

0.99

MPC

1.2

ClinPred

0.99

GERP RS

5.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.98

gMVP

0.97

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over