rs750614500

Variant names:

• chr22-40358949-C-G
• NM_000026.4:c.568C>G

Your query was ambiguous. Multiple possible variants found:

• chr22-40358949-C-G
• chr22-40358949-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PP3_Moderate PP5

The NM_000026.4(ADSL):​c.568C>G​(p.Arg190Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ADSL NM_000026.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1
• Conservation: PhyloP100: 3.31

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 Uncertain_significance. Variant got 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.874
• PP5: Variant 22-40358949-C-G is Pathogenic according to our data. Variant chr22-40358949-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 2725586.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ADSL	NM_000026.4	c.568C>G	p.Arg190Gly	missense_variant	Exon 5 of 13	ENST00000623063.3	NP_000017.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ADSL	ENST00000623063.3	c.568C>G	p.Arg190Gly	missense_variant	Exon 5 of 13	1	NM_000026.4	ENSP00000485525.1
ENSG00000284431	ENST00000639722.1	n.*264C>G		non_coding_transcript_exon_variant	Exon 4 of 31	5		ENSP00000492828.1
ENSG00000284431	ENST00000639722.1	n.*264C>G		3_prime_UTR_variant	Exon 4 of 31	5		ENSP00000492828.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Adenylosuccinate lyase deficiency Pathogenic:1 Uncertain:1

Dec 20, 2023

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Likely Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with adenylosuccinase deficiency (MIM#103050). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to glycine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v3) (9 heterozygotes, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated lyase_1 domain (DECIPHER). (I) 0703 - Another missense variant comparable to the one identified in this case has moderate previous evidence for pathogenicity. This alternative change (p.(Arg190Gln)) has been reported as likely pathogenic and pathogenic, and observed in several compound heterozygous individuals with moderate intellectual disability or hypotonia, oligofrenia and psychomotor impairment (ClinVar, PMID: 10090474, PMID: 10888601). (SP) 0807 - This variant has no previous evidence of pathogenicity. (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1101 - Very strong and specific phenotype match for this individual. (SP) 1201 - Heterozygous variant detected in trans with a second likely pathogenic heterozygous variant (p.(Gln439*)) in a recessive disease. (SP) 1205 - This variant has been shown to be maternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Jun 23, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. This variant disrupts the p.Arg190 amino acid residue in ADSL. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10090474, 10888601). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on ADSL protein function. This missense change has been observed in individual(s) with ADSL-related conditions (Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 190 of the ADSL protein (p.Arg190Gly). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.50
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.25
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.12	T;D;.;T;T;T;T;.
Eigen	Pathogenic	0.69
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Pathogenic	0.98	D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.49	D
MetaRNN	Pathogenic	0.87	D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.9	.;H;H;.;.;.;.;.
PrimateAI	Benign	0.41	T
PROVEAN	Pathogenic	-5.4	.;.;D;.;.;.;.;.
REVEL	Pathogenic	0.72
Sift	Benign	0.087	.;.;T;.;.;.;.;.
Sift4G	Benign	0.37	T;T;T;.;T;T;.;.
Polyphen		0.60, 0.98	.;P;D;.;.;.;.;.
Vest4		0.75, 0.71, 0.72
MutPred		0.66		.;.;.;.;Loss of MoRF binding (P = 0.0444);.;.;.;
MVP		0.99
MPC		0.63
ClinPred		0.97	D
GERP RS		6.0
Varity_R		0.92
gMVP		0.96

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr22-40754953;