rs17001863

Variant names:

• chr22-40363304-A-G
• rs17001863
• NM_000026.4:c.1101+233A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000026.4(ADSL):​c.1101+233A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.121 in 152,226 control chromosomes in the GnomAD database, including 1,221 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency: Genomes: 𝑓 0.12 (1221 hom., cov: 32)
• Consequence: ADSL NM_000026.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.412
• Publications: 4 publications found

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)

ENSG00000284431 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 22-40363304-A-G is Benign according to our data. Variant chr22-40363304-A-G is described in ClinVar as Benign. ClinVar VariationId is 678102.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.141 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADSL	NM_000026.4	MANE Select	c.1101+233A>G		intron	N/A	NP_000017.1
	ADSL	NM_001410812.1		c.1101+233A>G		intron	N/A	NP_001397741.1
	ADSL	NM_001363840.3		c.1101+233A>G		intron	N/A	NP_001350769.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADSL	ENST00000623063.3	TSL:1 MANE Select	c.1101+233A>G		intron	N/A	ENSP00000485525.1
	ADSL	ENST00000342312.9	TSL:1	c.1101+233A>G		intron	N/A	ENSP00000341429.6
	ADSL	ENST00000480775.3	TSL:1	n.*495+233A>G		intron	N/A	ENSP00000485462.2

Frequencies

GnomAD3 genomes AF: 0.121 AC: 18407 AN: 152106 Hom.: 1214 Cov.: 32

Gnomad AFR AF: 0.103

Gnomad AMI AF: 0.154

Gnomad AMR AF: 0.0704

Gnomad ASJ AF: 0.0899

Gnomad EAS AF: 0.0926

Gnomad SAS AF: 0.149

Gnomad FIN AF: 0.201

Gnomad MID AF: 0.111

Gnomad NFE AF: 0.133

Gnomad OTH AF: 0.103

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.121 AC: 18429 AN: 152226 Hom.: 1221 Cov.: 32 AF XY: 0.124 AC XY: 9239 AN XY: 74424

African (AFR) AF: 0.102 AC: 4254 AN: 41536

American (AMR) AF: 0.0703 AC: 1076 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0899 AC: 312 AN: 3470

East Asian (EAS) AF: 0.0924 AC: 479 AN: 5184

South Asian (SAS) AF: 0.151 AC: 726 AN: 4822

European-Finnish (FIN) AF: 0.201 AC: 2123 AN: 10584

Middle Eastern (MID) AF: 0.105 AC: 31 AN: 294

European-Non Finnish (NFE) AF: 0.133 AC: 9055 AN: 68016

Other (OTH) AF: 0.110 AC: 233 AN: 2110

Alfa AF: 0.122 Hom.: 2354

Bravo AF: 0.108

Asia WGS AF: 0.161 AC: 559 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Jun 19, 2018

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.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	1.2
DANN	Benign	0.62
PhyloP100		-0.41
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs17001863; hg19: chr22-40759308;