22-40361520-A-G

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM1BP4_StrongBS1_Supporting

The NM_000026.4(ADSL):c.895A>G(p.Met299Val) variant causes a missense change. The variant allele was found at a frequency of 0.000151 in 1,614,222 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M299T) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00084 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000079 ( 0 hom. )

Consequence

ADSL
NM_000026.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:2

Conservation

PhyloP100: 6.76

Publications

3 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: ClinGen, G2P, Orphanet, Labcorp Genetics (formerly Invitae)

ADSL links:

ENSG00000284431 (HGNC:):

ENSG00000284431 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -3 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 12 uncertain in NM_000026.4

BP4

Computational evidence support a benign effect (MetaRNN=0.029456675).

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00084 (128/152336) while in subpopulation AFR AF = 0.00301 (125/41578). AF 95% confidence interval is 0.00258. There are 0 homozygotes in GnomAd4. There are 66 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

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
ADSL	NM_000026.4	MANE Select	c.895A>G	p.Met299Val	missense	Exon 9 of 13	NP_000017.1
ADSL	NM_001410812.1		c.895A>G	p.Met299Val	missense	Exon 9 of 14	NP_001397741.1
ADSL	NM_001363840.3		c.895A>G	p.Met299Val	missense	Exon 9 of 14	NP_001350769.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
ADSL	ENST00000623063.3	TSL:1 MANE Select	c.895A>G	p.Met299Val	missense	Exon 9 of 13	ENSP00000485525.1
ADSL	ENST00000342312.9	TSL:1	c.895A>G	p.Met299Val	missense	Exon 9 of 12	ENSP00000341429.6
ADSL	ENST00000480775.3	TSL:1	n.*258A>G		non_coding_transcript_exon	Exon 9 of 13	ENSP00000485462.2

Frequencies

GnomAD3 genomes

AF:

0.000841

AC:

128

AN:

152218

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00302

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

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:

0.0000147

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.000243

AC:

AN:

251466

AF XY:

0.000199

show subpopulations

Gnomad AFR exome

AF:

0.00338

Gnomad AMR exome

AF:

0.000145

Gnomad ASJ exome

AF:

0.00

Gnomad EAS 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:

0.0000787

AC:

115

AN:

1461886

Hom.:

Cov.:

AF XY:

0.0000715

AC XY:

AN XY:

727244

show subpopulations

African (AFR)

AF:

0.00278

AC:

AN:

33480

American (AMR)

AF:

0.000134

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53416

Middle Eastern (MID)

AF:

0.000173

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000180

AC:

AN:

1112010

Other (OTH)

AF:

0.000215

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.489

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

AF:

0.000840

AC:

128

AN:

152336

Hom.:

Cov.:

AF XY:

0.000886

AC XY:

AN XY:

74496

show subpopulations

African (AFR)

AF:

0.00301

AC:

125

AN:

41578

American (AMR)

AF:

0.0000654

AC:

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68030

Other (OTH)

AF:

0.000473

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

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:

0.000335

Hom.:

Bravo

AF:

0.000937

ESP6500AA

AF:

0.00227

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000247

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:3

Nov 04, 2020

Athena Diagnostics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Jul 05, 2018

Eurofins Ntd Llc (ga)

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Dec 28, 2023

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge

Adenylosuccinate lyase deficiency

Uncertain:1Benign:1

Jan 27, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Mar 28, 2023

Baylor Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

ADSL-related disorder

Benign:1

Jun 06, 2023

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.30

BayesDel_addAF

Uncertain

0.074

BayesDel_noAF

Pathogenic

0.33

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.82

Eigen

Uncertain

0.46

Eigen_PC

Uncertain

0.49

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

0.98

M_CAP

Pathogenic

0.63

MetaRNN

Benign

0.029

MetaSVM

Pathogenic

1.0

MutationAssessor

Uncertain

2.8

PhyloP100

6.8

PrimateAI

Uncertain

0.61

PROVEAN

Uncertain

-3.8

REVEL

Pathogenic

0.81

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.012

Polyphen

0.76

Vest4

0.76

MVP

0.98

MPC

0.72

ClinPred

0.14

GERP RS

4.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.89

gMVP

0.83

Mutation Taster

=15/85

disease causing

(source)

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

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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

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over