rs11089991

Positions:

chr22-40354285-A-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The ENST00000623063.3(ADSL):c.440A>T(p.Lys147Met) variant causes a missense change. The variant allele was found at a frequency of 0.00245 in 1,614,214 control chromosomes in the GnomAD database, including 79 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K147E) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.013 ( 37 hom., cov: 31)

Exomes 𝑓: 0.0013 ( 42 hom. )

Consequence

ADSL
ENST00000623063.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: 4.97

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 Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0056613684).

BP6

Variant 22-40354285-A-T is Benign according to our data. Variant chr22-40354285-A-T is described in ClinVar as [Benign]. Clinvar id is 128278.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-40354285-A-T is described in Lovd as [Likely_benign]. Variant chr22-40354285-A-T is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0131 (1989/152342) while in subpopulation AFR AF= 0.0453 (1884/41558). AF 95% confidence interval is 0.0436. There are 37 homozygotes in gnomad4. There are 952 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 37 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ADSL	NM_000026.4 linkuse as main transcript	c.440A>T	p.Lys147Met	missense_variant	4/13	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.440A>T	p.Lys147Met	missense_variant	4/13	1	NM_000026.4	ENSP00000485525	P1	P30566-1

Frequencies

GnomAD3 genomes

AF:

0.0130

AC:

1979

AN:

152224

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0452

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00464

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000191

Gnomad OTH

AF:

0.00908

GnomAD3 exomes

AF:

0.00337

AC:

847

AN:

251494

Hom.:

AF XY:

0.00234

AC XY:

318

AN XY:

135922

show subpopulations

Gnomad AFR exome

AF:

0.0467

Gnomad AMR exome

AF:

0.00199

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000653

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000703

Gnomad OTH exome

AF:

0.00147

GnomAD4 exome

AF:

0.00134

AC:

1964

AN:

1461872

Hom.:

Cov.:

AF XY:

0.00111

AC XY:

810

AN XY:

727238

show subpopulations

Gnomad4 AFR exome

AF:

0.0473

Gnomad4 AMR exome

AF:

0.00235

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000464

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000764

Gnomad4 OTH exome

AF:

0.00300

GnomAD4 genome

AF:

0.0131

AC:

1989

AN:

152342

Hom.:

Cov.:

AF XY:

0.0128

AC XY:

952

AN XY:

74494

show subpopulations

Gnomad4 AFR

AF:

0.0453

Gnomad4 AMR

AF:

0.00464

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000414

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000191

Gnomad4 OTH

AF:

0.00899

Alfa

AF:

0.00194

Hom.:

Bravo

AF:

0.0151

ESP6500AA

AF:

0.0456

AC:

201

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.00409

AC:

496

Asia WGS

AF:

0.00289

AC:

AN:

3478

EpiCase

AF:

0.000218

EpiControl

AF:

0.0000593

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 18, 2012	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided

Benign:4

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Apr 11, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jan 13, 2017	- -

Adenylosuccinate lyase deficiency

Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 30, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.20

BayesDel_addAF

Benign

-0.26

BayesDel_noAF

Benign

-0.12

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.012

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

Eigen

Benign

-0.21

Eigen_PC

Benign

0.026

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

0.98

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

MetaRNN

Benign

0.0057

T;T;T;T;T;T;T

MetaSVM

Uncertain

0.25

MutationAssessor

Benign

0.40

.;N;N;.;.;.;.

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Benign

0.35

PROVEAN

Benign

-1.8

.;.;N;.;.;.;.

REVEL

Uncertain

0.42

Sift

Benign

0.15

.;.;T;.;.;.;.

Sift4G

Benign

0.15

T;T;T;.;T;.;.

Polyphen

0.0040, 0.0010

.;B;B;.;.;.;.

Vest4

0.47, 0.45, 0.44

MVP

0.96

MPC

0.41

ClinPred

0.029

GERP RS

3.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.22

gMVP

0.80

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