rs568567422

chr22-40364295-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 6P and 2B. PM1 PM2 PM5 BP4_Moderate

The NM_000026.4(ADSL):c.1121G>A(p.Arg374Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000143 in 1,613,874 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. 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. R374W) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.000039 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: ADSL NM_000026.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 2.44

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 2 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
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr22-40364294-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 381550.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=1, Uncertain_significance=1}.
• BP4: Computational evidence support a benign effect (MetaRNN=0.08151835).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ADSL	NM_000026.4	c.1121G>A	p.Arg374Gln	missense_variant	11/13	ENST00000623063.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ADSL	ENST00000623063.3	c.1121G>A	p.Arg374Gln	missense_variant	11/13	1	NM_000026.4	P1

Frequencies

GnomAD3 genomes AF: 0.0000395 AC: 6 AN: 152046 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000199 AC: 5 AN: 251346 Hom.: 0 AF XY: 0.0000147 AC XY: 2 AN XY: 135840

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000654

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000116 AC: 17 AN: 1461710 Hom.: 0 Cov.: 31 AF XY: 0.0000124 AC XY: 9 AN XY: 727146

Gnomad4 AFR exome AF: 0.0000896

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000809

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.0000394 AC: 6 AN: 152164 Hom.: 0 Cov.: 32 AF XY: 0.0000403 AC XY: 3 AN XY: 74386

Gnomad4 AFR AF: 0.000145

Gnomad4 AMR AF: 0.00

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

Alfa AF: 0.0000329 Hom.: 0

Bravo AF: 0.0000491

ExAC AF: 0.0000247 AC: 3

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Nov 28, 2017

A variant of uncertain significance has been identified in the ADSL gene. The R374Q variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. A different missense substitution at the same position (R374W) has been reported in an individual with seizures, intellectual disability, facial dysmorphism, and biochemical testing consistent with ADSL deficiency; this individual also had a second ADSL variant on the opposite allele (Holder-Espinasse et al., 2002). The R374Q variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The R374Q variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. However, this substitution occurs at a position that is not conserved. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant. -

Adenylosuccinate lyase deficiency Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Aug 20, 2022

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 374 of the ADSL protein (p.Arg374Gln). This variant is present in population databases (rs568567422, gnomAD 0.02%). 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: 423931). 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. This variant disrupts the p.Arg374 amino acid residue in ADSL. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 12070256; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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	Benign	0.069
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.20
Cadd	Benign	21
Dann	Benign	0.92
DEOGEN2	Benign	0.16	T;.;T;T;T
Eigen	Benign	-0.71
Eigen_PC	Benign	-0.53
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.93	D;D;D;D;D
M_CAP	Benign	0.079	D
MetaRNN	Benign	0.082	T;T;T;T;T
MetaSVM	Benign	-0.43	T
MutationAssessor	Benign	0.47	N;N;.;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Benign	0.37	T
Sift4G	Benign	0.61	T;T;.;T;.
Polyphen		0.019	B;B;.;.;.
Vest4		0.42
MVP		0.78
MPC		0.34
ClinPred		0.066	T
GERP RS		1.1
Varity_R		0.12
gMVP		0.73

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: rs568567422; hg19: chr22-40760299;