rs8135371

Positions:

• chr22-40361224-A-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_000026.4(ADSL):​c.793-49A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.14 in 1,559,676 control chromosomes in the GnomAD database, including 16,243 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.13 (1398 hom., cov: 32)
  • Exomes 𝑓: 0.14 (14845 hom.)
• Consequence: ADSL NM_000026.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.16

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]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.94).
• BP6: Variant 22-40361224-A-C is Benign according to our data. Variant chr22-40361224-A-C is described in ClinVar as [Benign]. Clinvar id is 670882.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.163 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ADSL	NM_000026.4	c.793-49A>C		intron_variant		ENST00000623063.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ADSL	ENST00000623063.3	c.793-49A>C		intron_variant		1	NM_000026.4	P1

Frequencies

GnomAD3 genomes AF: 0.130 AC: 19742 AN: 151924 Hom.: 1390 Cov.: 32

Gnomad AFR AF: 0.106

Gnomad AMI AF: 0.159

Gnomad AMR AF: 0.0776

Gnomad ASJ AF: 0.111

Gnomad EAS AF: 0.0959

Gnomad SAS AF: 0.171

Gnomad FIN AF: 0.221

Gnomad MID AF: 0.123

Gnomad NFE AF: 0.143

Gnomad OTH AF: 0.117

GnomAD3 exomes AF: 0.134 AC: 33625 AN: 251178 Hom.: 2612 AF XY: 0.140 AC XY: 18970 AN XY: 135776

Gnomad AFR exome AF: 0.103

Gnomad AMR exome AF: 0.0556

Gnomad ASJ exome AF: 0.109

Gnomad EAS exome AF: 0.0985

Gnomad SAS exome AF: 0.171

Gnomad FIN exome AF: 0.224

Gnomad NFE exome AF: 0.143

Gnomad OTH exome AF: 0.126

GnomAD4 exome AF: 0.141 AC: 199149 AN: 1407634 Hom.: 14845 Cov.: 25 AF XY: 0.144 AC XY: 101038 AN XY: 703538

Gnomad4 AFR exome AF: 0.103

Gnomad4 AMR exome AF: 0.0585

Gnomad4 ASJ exome AF: 0.110

Gnomad4 EAS exome AF: 0.0905

Gnomad4 SAS exome AF: 0.172

Gnomad4 FIN exome AF: 0.211

Gnomad4 NFE exome AF: 0.144

Gnomad4 OTH exome AF: 0.129

GnomAD4 genome AF: 0.130 AC: 19768 AN: 152042 Hom.: 1398 Cov.: 32 AF XY: 0.134 AC XY: 9966 AN XY: 74310

Gnomad4 AFR AF: 0.106

Gnomad4 AMR AF: 0.0775

Gnomad4 ASJ AF: 0.111

Gnomad4 EAS AF: 0.0957

Gnomad4 SAS AF: 0.173

Gnomad4 FIN AF: 0.221

Gnomad4 NFE AF: 0.143

Gnomad4 OTH AF: 0.124

Alfa AF: 0.135 Hom.: 2195

Bravo AF: 0.115

Asia WGS AF: 0.171 AC: 593 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 14, 2018

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 v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	0.33
DANN	Benign	0.60

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

LitVar

Other links and lift over

dbSNP: rs8135371; hg19: chr22-40757228; COSMIC: COSV53407130; COSMIC: COSV53407130;