Genetic Variant ADSL:p.Arg426His (chr22-40364965-G-A) – ACMG Classification: Pathogenic (18 pts)

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PS3PM1PM5PP3_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 (★★). ClinVar reports functional evidence for this variant: "SCV000438687: 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" and additional evidence is available in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R426C) has been classified as Likely 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:22

Conservation

PhyloP100: 8.88

Publications

28 publications found

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 Gene-Disease associations (from GenCC):

adenylosuccinate lyase deficiency
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, Orphanet, G2P

ADSL links:

ENSG00000284431 (HGNC:):

ENSG00000284431 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 18 ACMG points.

PS3

PS3 evidence extracted from ClinVar submissions: SCV000438687: 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).; SCV000631362: Experimental studies have shown that this missense change affects ADSL function (PMID: 18524658, 20127976).; SCV000713087: "In vitro functional studies provide evidence supporting an impact on protein function (Barésova 2012 and Zikanova 2010)."; SCV005400847: Experimental analysis demonstrated this variant to cause reduced thermal stability and ADSL activity (Kmoch et al., 2000; Zikanova et al., 2010).; SCV000240259: Published functional studies demonstrate reduced enzyme activity (Jurecka et al., 2008; Ray et al., 2013; Zikanova et al., 2010); SCV003677029: In vitro analysis demonstrated reduced thermal stability and ADSL activity (Kmoch, 2000; Zikanova, 2010).

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 7 uncertain in NM_000026.4

PM5

Other missense variant is known to change same aminoacid residue: Variant chr22-40364964-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 204798.

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 VariationId is 2462.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000026.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ADSL	NM_000026.4	MANE Select	c.1277G>A	p.Arg426His	missense	Exon 12 of 13	NP_000017.1	X5D8S6
ADSL	NM_001410812.1		c.1277G>A	p.Arg426His	missense	Exon 12 of 14	NP_001397741.1	A0A7P0Z472
ADSL	NM_001363840.3		c.1277G>A	p.Arg426His	missense	Exon 12 of 14	NP_001350769.1	A0A1B0GWJ0

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ADSL	ENST00000623063.3	TSL:1 MANE Select	c.1277G>A	p.Arg426His	missense	Exon 12 of 13	ENSP00000485525.1	P30566-1
ADSL	ENST00000342312.9	TSL:1	c.1191+600G>A		intron	N/A	ENSP00000341429.6	P30566-2
ADSL	ENST00000480775.3	TSL:1	n.*671G>A		non_coding_transcript_exon	Exon 12 of 13	ENSP00000485462.2	A0A096LP92

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

GnomAD2 exomes

AF:

0.000199

AC:

AN:

251490

AF XY:

0.000199

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 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

African (AFR)

AF:

0.0000896

AC:

AN:

33478

American (AMR)

AF:

0.000112

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.0000696

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000333

AC:

370

AN:

1111912

Other (OTH)

AF:

0.000248

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

115

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000223

AC:

AN:

152146

Hom.:

Cov.:

AF XY:

0.000188

AC XY:

AN XY:

74306

show subpopulations

African (AFR)

AF:

0.0000483

AC:

AN:

41440

American (AMR)

AF:

0.00

AC:

AN:

15264

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5194

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10598

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000470

AC:

AN:

68034

Other (OTH)

AF:

0.00

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000342

Hom.:

Bravo

AF:

0.000215

ExAC

AF:

0.000255

AC:

EpiCase

AF:

0.000382

EpiControl

AF:

0.000237

ClinVar

ClinVar submissions

Significance:Pathogenic

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Adenylosuccinate lyase deficiency (12)

not provided (9)

Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.43

BayesDel_addAF

Pathogenic

0.28

BayesDel_noAF

Pathogenic

0.48

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.87

Eigen

Uncertain

0.67

Eigen_PC

Pathogenic

0.71

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.95

M_CAP

Uncertain

0.22

MetaRNN

Pathogenic

0.85

MetaSVM

Pathogenic

1.0

MutationAssessor

Pathogenic

3.4

PhyloP100

8.9

PrimateAI

Uncertain

0.59

REVEL

Pathogenic

0.90

Sift4G

Uncertain

0.046

Polyphen

0.46

Vest4

0.87

MVP

0.86

MPC

0.45

ClinPred

0.80

GERP RS

5.7

PromoterAI

-0.023

Neutral

(source)

Varity_R

0.95

gMVP

0.85

Mutation Taster

=1/99

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over