rs778401578

chr22-40364288-C-Achr22-40364288-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1 PM2

The NM_000026.4(ADSL):c.1114C>A(p.Arg372Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000496 in 1,613,776 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R372H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: ADSL NM_000026.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.33

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 Uncertain_significance. Variant got 4 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 7 uncertain in NM_000026.4
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ADSL	NM_000026.4	c.1114C>A	p.Arg372Ser	missense_variant	11/13	ENST00000623063.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ADSL	ENST00000623063.3	c.1114C>A	p.Arg372Ser	missense_variant	11/13	1	NM_000026.4	P1

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152138 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

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: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000159 AC: 4 AN: 251340 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135840

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000868

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS 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: 0.00000410 AC: 6 AN: 1461638 Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3 AN XY: 727118

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000671

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152138 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74308

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000113

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Adenylosuccinate lyase deficiency Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Nov 27, 2023

This sequence change replaces arginine, which is basic and polar, with serine, which is neutral and polar, at codon 372 of the ADSL protein (p.Arg372Ser). This variant is present in population databases (rs778401578, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with ADSL-related conditions. ClinVar contains an entry for this variant (Variation ID: 574285). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt ADSL protein function with a negative predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.81
BayesDel_addAF	Uncertain	0.037	T
BayesDel_noAF	Uncertain	0.010
Cadd	Uncertain	25
Dann	Uncertain	0.99
DEOGEN2	Uncertain	0.56	D;.;T;T;T
Eigen	Benign	0.17
Eigen_PC	Uncertain	0.26
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Pathogenic	0.98	D;D;D;D;D
M_CAP	Pathogenic	0.29	D
MetaRNN	Uncertain	0.60	D;D;D;D;D
MetaSVM	Uncertain	0.67	D
MutationAssessor	Uncertain	2.2	M;M;.;.;.
MutationTaster	Benign	0.99	D;D;D
PrimateAI	Benign	0.41	T
Sift4G	Uncertain	0.028	D;D;.;D;.
Polyphen		0.0060	B;B;.;.;.
Vest4		0.71
MutPred		0.57		.;.;.;Gain of phosphorylation at R386 (P = 0.0665);.;
MVP		0.97
MPC		0.34
ClinPred		0.77	D
GERP RS		4.5
Varity_R		0.77
gMVP		0.84

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: rs778401578; hg19: chr22-40760292;