rs1555907605

Variant names:

• chr22-40359260-G-A
• rs1555907605
• NM_000026.4:c.655G>A

Your query was ambiguous. Multiple possible variants found:

• chr22-40359260-G-A
• chr22-40359260-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_000026.4(ADSL):​c.655G>A​(p.Val219Ile) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ADSL NM_000026.4 missense, splice_region
• Scores: Splicing: ADA: 0.9989
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.29

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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ADSL	NM_000026.4	c.655G>A	p.Val219Ile	missense_variant, splice_region_variant	Exon 6 of 13	ENST00000623063.3	NP_000017.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ADSL	ENST00000623063.3	c.655G>A	p.Val219Ile	missense_variant, splice_region_variant	Exon 6 of 13	1	NM_000026.4	ENSP00000485525.1
ENSG00000284431	ENST00000639722.1	n.*351G>A		splice_region_variant, non_coding_transcript_exon_variant	Exon 5 of 31	5		ENSP00000492828.1
ENSG00000284431	ENST00000639722.1	n.*351G>A		3_prime_UTR_variant	Exon 5 of 31	5		ENSP00000492828.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Adenylosuccinate lyase deficiency Uncertain:1

Nov 21, 2022

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. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 459616). This variant has not been reported in the literature in individuals affected with ADSL-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 219 of the ADSL protein (p.Val219Ile). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Uncertain	0.065	T
BayesDel_noAF	Benign	-0.14
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Benign	0.038	T;D;.;T;T;T;T;.
Eigen	Pathogenic	0.87
Eigen_PC	Pathogenic	0.86
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	0.98	D;D;D;D;D;D;D;D
M_CAP	Benign	0.083	D
MetaRNN	Uncertain	0.45	T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.045	D
MutationAssessor	Uncertain	2.4	.;M;M;.;.;.;.;.
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-1.0	.;.;N;.;.;.;.;.
REVEL	Uncertain	0.38
Sift	Benign	0.19	.;.;T;.;.;.;.;.
Sift4G	Benign	0.23	T;T;T;.;T;T;.;.
Polyphen		1.0, 0.98	.;D;D;.;.;.;.;.
Vest4		0.33, 0.32, 0.33
MutPred		0.54		.;.;.;.;Loss of ubiquitination at K238 (P = 0.0645);.;.;.;
MVP		0.89
MPC		0.87
ClinPred		0.89	D
GERP RS		6.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.8
Varity_R		0.66
gMVP		0.85

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.95
SpliceAI score (max)		0.16		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: rs1555907605; hg19: chr22-40755264;