rs2228415

Variant names:

• chr22-40346682-C-T
• rs2228415
• NM_000026.4:c.124C>T

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BS1 BS2

The NM_000026.4(ADSL):​c.124C>T​(p.Leu42Leu) variant causes a synonymous change. The variant allele was found at a frequency of 0.013 in 1,611,704 control chromosomes in the GnomAD database, including 163 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0094 (9 hom., cov: 32)
  • Exomes 𝑓: 0.013 (154 hom.)
• Consequence: ADSL NM_000026.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 4.87

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]

ENSG00000284431 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.32).
• BP6: Variant 22-40346682-C-T is Benign according to our data. Variant chr22-40346682-C-T is described in ClinVar as [Benign]. Clinvar id is 128276.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-40346682-C-T is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00935 (1425/152342) while in subpopulation NFE AF= 0.0151 (1028/68036). AF 95% confidence interval is 0.0143. There are 9 homozygotes in gnomad4. There are 682 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 9 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ADSL	NM_000026.4	c.124C>T	p.Leu42Leu	synonymous_variant	Exon 1 of 13	ENST00000623063.3	NP_000017.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ADSL	ENST00000623063.3	c.124C>T	p.Leu42Leu	synonymous_variant	Exon 1 of 13	1	NM_000026.4	ENSP00000485525.1
ENSG00000284431	ENST00000639722.1	n.124C>T		non_coding_transcript_exon_variant	Exon 1 of 31	5		ENSP00000492828.1

Frequencies

GnomAD3 genomes AF: 0.00935 AC: 1424 AN: 152224 Hom.: 9 Cov.: 32

Gnomad AFR AF: 0.00234

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00962

Gnomad ASJ AF: 0.00375

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.0104

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0151

Gnomad OTH AF: 0.0115

GnomAD3 exomes AF: 0.00944 AC: 2303 AN: 243966 Hom.: 25 AF XY: 0.00934 AC XY: 1241 AN XY: 132888

Gnomad AFR exome AF: 0.00226

Gnomad AMR exome AF: 0.00870

Gnomad ASJ exome AF: 0.00473

Gnomad EAS exome AF: 0.0000549

Gnomad SAS exome AF: 0.000197

Gnomad FIN exome AF: 0.0125

Gnomad NFE exome AF: 0.0146

Gnomad OTH exome AF: 0.0114

GnomAD4 exome AF: 0.0134 AC: 19586 AN: 1459362 Hom.: 154 Cov.: 31 AF XY: 0.0130 AC XY: 9438 AN XY: 726052

Gnomad4 AFR exome AF: 0.00203

Gnomad4 AMR exome AF: 0.00908

Gnomad4 ASJ exome AF: 0.00552

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000244

Gnomad4 FIN exome AF: 0.0122

Gnomad4 NFE exome AF: 0.0159

Gnomad4 OTH exome AF: 0.0108

GnomAD4 genome AF: 0.00935 AC: 1425 AN: 152342 Hom.: 9 Cov.: 32 AF XY: 0.00915 AC XY: 682 AN XY: 74498

Gnomad4 AFR AF: 0.00236

Gnomad4 AMR AF: 0.00961

Gnomad4 ASJ AF: 0.00375

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.0104

Gnomad4 NFE AF: 0.0151

Gnomad4 OTH AF: 0.0113

Alfa AF: 0.0119 Hom.: 7

Bravo AF: 0.00956

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.0147

EpiControl AF: 0.0158

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Jun 09, 2014

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 20, 2012

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Jun 29, 2017

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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. -

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Aug 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ADSL: BP4, BS1, BS2 -

Adenylosuccinate lyase deficiency Benign:2

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.32
CADD	Benign	15
DANN	Benign	0.97

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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

Other links and lift over

dbSNP: rs2228415; hg19: chr22-40742686; COSMIC: COSV53407421; COSMIC: COSV53407421;