rs773071023

Positions:

• chr7-66092817-G-T

Variant summary

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

The ENST00000304874.14(ASL):​c.1300G>T​(p.Val434Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000616 in 1,461,522 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. V434V) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000062 (0 hom.)
• Consequence: ASL ENST00000304874.14 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:2
• Conservation: PhyloP100: 8.54

Genes affected

ASL (HGNC:746): (argininosuccinate lyase) This gene encodes a member of the lyase 1 family. The encoded protein forms a cytosolic homotetramer and primarily catalyzes the reversible hydrolytic cleavage of argininosuccinate into arginine and fumarate, an essential step in the liver in detoxifying ammonia via the urea cycle. Mutations in this gene result in the autosomal recessive disorder argininosuccinic aciduria, or argininosuccinic acid lyase deficiency. A nontranscribed pseudogene is also located on the long arm of chromosome 22. Alternatively spliced transcript variants encoding different isoforms have been described. [provided by RefSeq, Jul 2008]

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, 0.898
• PP5: Variant 7-66092817-G-T is Pathogenic according to our data. Variant chr7-66092817-G-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 557968.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Pathogenic=1, Uncertain_significance=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ASL	NM_000048.4	c.1300G>T	p.Val434Leu	missense_variant	17/17	ENST00000304874.14	NP_000039.2
ASL	NM_001024943.2	c.1300G>T	p.Val434Leu	missense_variant	16/16		NP_001020114.1
ASL	NM_001024944.2	c.1240G>T	p.Val414Leu	missense_variant	15/15		NP_001020115.1
ASL	NM_001024946.2	c.1222G>T	p.Val408Leu	missense_variant	15/15		NP_001020117.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ASL	ENST00000304874.14	c.1300G>T	p.Val434Leu	missense_variant	17/17	1	NM_000048.4	ENSP00000307188	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000399 AC: 1 AN: 250932 Hom.: 0 AF XY: 0.00000737 AC XY: 1 AN XY: 135738

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000616 AC: 9 AN: 1461522 Hom.: 0 Cov.: 32 AF XY: 0.00000963 AC XY: 7 AN XY: 727088

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000927

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Argininosuccinate lyase deficiency Pathogenic:2 Uncertain:1

Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Sep 06, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Apr 20, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 13, 2023	This sequence change replaces valine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 434 of the ASL protein (p.Val434Leu). This variant is present in population databases (rs773071023, gnomAD 0.003%). This missense change has been observed in individual(s) with argininosuccinic aciduria (PMID: 24166829, 30285816). ClinVar contains an entry for this variant (Variation ID: 557968). 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 expected to disrupt ASL protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic. -

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 22, 2022

The c.1300G>T (p.V434L) alteration is located in exon 17 (coding exon 16) of the ASL gene. This alteration results from a G to T substitution at nucleotide position 1300, causing the valine (V) at amino acid position 434 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.72
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.31
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.93	D;.;D;.
Eigen	Pathogenic	0.69
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.98	.;D;D;D
M_CAP	Pathogenic	0.88	D
MetaRNN	Pathogenic	0.90	D;D;D;D
MetaSVM	Pathogenic	0.84	D
MutationAssessor	Benign	1.9	L;.;L;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.71	T
PROVEAN	Uncertain	-2.5	D;D;D;D
REVEL	Pathogenic	0.92
Sift	Benign	0.035	D;D;D;D
Sift4G	Uncertain	0.014	D;D;D;D
Polyphen		0.99	D;.;D;.
Vest4		0.79
MutPred		0.51		Loss of helix (P = 0.1299);.;Loss of helix (P = 0.1299);.;
MVP		0.93
MPC		0.70
ClinPred		0.89	D
GERP RS		5.6
Varity_R		0.84
gMVP		0.82

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: rs773071023; hg19: chr7-65557804;