rs119450941

Positions:

chr22-40364965-G-A

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1PM2PP3_ModeratePP5_Very_Strong

The NM_000026.4(ADSL):c.1277G>A(p.Arg426His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000268 in 1,613,934 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 Pathogenic (★★).

Frequency

Genomes: 𝑓 0.00022 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00027 ( 0 hom. )

Consequence

ADSL
NM_000026.4 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:19

Conservation

PhyloP100: 8.88

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 14 ACMG points.

PM1

In a helix (size 6) in uniprot entity PUR8_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_000026.4

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.855

PP5

Variant 22-40364965-G-A is Pathogenic according to our data. Variant chr22-40364965-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 2462.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-40364965-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ADSL	NM_000026.4 linkuse as main transcript	c.1277G>A	p.Arg426His	missense_variant	12/13	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.1277G>A	p.Arg426His	missense_variant	12/13	1	NM_000026.4	ENSP00000485525	P1	P30566-1

Frequencies

GnomAD3 genomes

AF:

0.000223

AC:

AN:

152146

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

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:

0.000470

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000199

AC:

AN:

251490

Hom.:

AF XY:

0.000199

AC XY:

AN XY:

135920

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.000116

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.000360

Gnomad OTH exome

AF:

0.000326

GnomAD4 exome

AF:

0.000273

AC:

399

AN:

1461788

Hom.:

Cov.:

AF XY:

0.000283

AC XY:

206

AN XY:

727198

show subpopulations

Gnomad4 AFR exome

AF:

0.0000896

Gnomad4 AMR exome

AF:

0.000112

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000696

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000333

Gnomad4 OTH exome

AF:

0.000248

GnomAD4 genome

AF:

0.000223

AC:

AN:

152146

Hom.:

Cov.:

AF XY:

0.000188

AC XY:

AN XY:

74306

show subpopulations

Gnomad4 AFR

AF:

0.0000483

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:

0.000470

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000337

Hom.:

Bravo

AF:

0.000215

ExAC

AF:

0.000255

AC:

EpiCase

AF:

0.000382

EpiControl

AF:

0.000237

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:19

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Adenylosuccinate lyase deficiency

Pathogenic:10

Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Sep 12, 2017	The p.Arg426His (NM_000026.2 c.1277G>A) variant in ADSL has been reported in 11 homozygotes and 9 compound heterozygous individuals with Adenylosuccinate lyase deficiency (ADSL) (Cantwell 1988, Marie 1999, Kmoch 2000, Mouchegh 2007, Jurecka 2008, Lundy 2010, Henneke 2010, Jurecka 2016 and Donti 2016), and segregated in 3 family members in 2 families (Edery 2003 Donti 2016), and has been reported i n ClinVar (Variation ID#2462) by multiple laboratories as pathogenic. In vitro f unctional studies provide evidence supporting an impact on protein function (Bar esova 2012 and Zikanova 2010). This variant has been identified in 0.042% (28/66 ,740) of European chromosomes by the Exome Aggregation Consortium (ExAC, http:// exac.broadinstitute.org; dbSNP rs119450941). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. In summary, this variant meets criteria to be class ified as pathogenic for ADSL in an autosomal recessive manner based upon biallel ic case observations, segregation in affected individuals and functional evidenc e. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Aug 01, 2008	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jul 16, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	Courtagen Diagnostics Laboratory, Courtagen Life Sciences	Dec 28, 2013	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Sep 14, 2023	Criteria applied: PM3_VSTR,PM5,PM2_SUP,PP3 -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jun 14, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 31, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 21, 2024	Variant summary: ADSL c.1277G>A (p.Arg426His) results in a non-conservative amino acid change located in the Adenylosuccinate lyase C-terminal domain (IPR019468) 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 0.0002 in 251490 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in ADSL causing Adenylosuccinate Lyase Deficiency, allowing no conclusion about variant significance. c.1277G>A has been reported in the literature in multiple hompozygous and compound heterozygous individuals affected with Adenylosuccinate Lyase Deficiency (Edery_2003, Mouchegh_2007). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 12833398, 17188615). ClinVar contains an entry for this variant (Variation ID: 2462). Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 23, 2024	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 426 of the ADSL protein (p.Arg426His). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individuals with adenylosuccinate lyase deficiency (PMID: 10090474, 12833398, 16839792, 18524658, 25112391, 27504266). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 2462). 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: 18524658, 20127976). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	The ADSL c.1277G>A (p.Arg426His) variant has been identified in a homozygous state in 13 individuals with adenylosuccinase deficiency, in a compound heterozygous state in four individuals, and in a heterozygous state in six unaffected family members (Marie et al. 1999; Kmoch et al. 2000; Edery et al. 2003; Jurecka et al. 2008; Donti et al. 2016). The p.Arg426His variant was absent from 88 controls and is reported at a frequency of 0.00042 in the European (non-Finnish) population of the Exome Aggregation Consortium. In vitro functional studies demonstrated that the p.Arg426His mutant enzyme resulted in approximately 50% of wild type activity. Biochemical analyses showed that the p.Arg426His variant produced an unstable protein (Kmoch et al. 2000; Jurecka et al. 2008; Zikanova et al. 2010). Based on the collective evidence, the p.Arg426His variant is classified as pathogenic for adenylosuccinase deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

not provided

Pathogenic:8

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 16, 2022	Published functional studies demonstrate reduced enzyme activity (Jurecka et al., 2008; Ray et al., 2013; Zikanova et al., 2010); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 20127976, 29655203, 31164858, 10958654, 23714113, 10888601, 10090474, 7334371, 18524658, 16839792, 23504561, 27504266, 12833398, 30609409, 31729379, 34426522, 34582790, 33497949, 31589614, 33648541) -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 26, 2014	- -
Pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Nov 28, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratoire Génétique Moléculaire, CHRU TOURS	Mar 31, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	AiLife Diagnostics, AiLife Diagnostics	Jun 17, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jan 30, 2017	- -

Inborn genetic diseases

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 02, 2021

The c.1277G>A (p.R426H) alteration is located in exon 12 (coding exon 12) of the ADSL gene. This alteration results from a G to A substitution at nucleotide position 1277, causing the arginine (R) at amino acid position 426 to be replaced by a histidine (H). Based on data from the Genome Aggregation Database (gnomAD), the ADSL c.1277G>A alteration was observed in 0.02% (51/282896) of total alleles studied, with a frequency of 0.03% (42/129196) in the European (non-Finnish) subpopulation. This mutation is the most common mutation occurring in about 30% of affected individuals; it has been identified in the homozygous and compound heterozygous state in multiple individuals with adenylosuccinase deficiency (Ray, 2013; Jurecka, 2014; Donti, 2016; Mastrogiorgio, 2021). In vitro analysis demonstrated reduced thermal stability and ADSL activity (Kmoch, 2000; Zikanova, 2010). The p.R426H alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.43

BayesDel_addAF

Pathogenic

0.28

BayesDel_noAF

Pathogenic

0.48

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.87

D;T;T

Eigen

Uncertain

0.67

Eigen_PC

Pathogenic

0.71

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.95

D;D;D

M_CAP

Uncertain

0.22

MetaRNN

Pathogenic

0.85

D;D;D

MetaSVM

Pathogenic

1.0

MutationAssessor

Pathogenic

3.4

M;.;.

MutationTaster

Benign

1.0

A;A;A

PrimateAI

Uncertain

0.59

REVEL

Pathogenic

0.90

Sift4G

Uncertain

0.046

D;.;D

Polyphen

0.46

P;.;.

Vest4

0.87

MVP

0.86

MPC

0.45

ClinPred

0.80

GERP RS

5.7

Varity_R

0.95

gMVP

0.85

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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