rs796051931

Positions:

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1PM2PM5PP3_ModeratePP5

The ENST00000304874.14(ASL):c.437G>A(p.Arg146Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000682 in 1,612,560 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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R146P) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000068 ( 0 hom. )

Consequence

ASL
ENST00000304874.14 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3U:1

Conservation

PhyloP100: 8.85

Variant links:

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]

ASL links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

PM1

In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 2 uncertain in ENST00000304874.14

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr7-66083164-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 203626.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.849

PP5

Variant 7-66083165-G-A is Pathogenic according to our data. Variant chr7-66083165-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 203627.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Pathogenic=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
ASL	NM_000048.4 linkuse as main transcript	c.437G>A	p.Arg146Gln	missense_variant	6/17	ENST00000304874.14	NP_000039.2
ASL	NM_001024943.2 linkuse as main transcript	c.437G>A	p.Arg146Gln	missense_variant	5/16		NP_001020114.1
ASL	NM_001024944.2 linkuse as main transcript	c.437G>A	p.Arg146Gln	missense_variant	5/15		NP_001020115.1
ASL	NM_001024946.2 linkuse as main transcript	c.437G>A	p.Arg146Gln	missense_variant	5/15		NP_001020117.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ASL	ENST00000304874.14 linkuse as main transcript	c.437G>A	p.Arg146Gln	missense_variant	6/17	1	NM_000048.4	ENSP00000307188	P1	P04424-1

Frequencies

GnomAD3 genomes

AF:

0.00000658

AC:

AN:

152054

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000685

AC:

AN:

1460506

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

726520

show subpopulations

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:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000899

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000658

AC:

AN:

152054

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74276

show subpopulations

Gnomad4 AFR

AF:

0.00

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:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000113

EpiCase

AF:

0.0000545

EpiControl

AF:

0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Argininosuccinate lyase deficiency

Pathogenic:3Uncertain:1

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 14, 2023	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 146 of the ASL protein (p.Arg146Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with argininosuccinate lyase deficiency (PMID: 28251416). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 203627). 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%. This variant disrupts the p.Arg146 amino acid residue in ASL. Other variant(s) that disrupt this residue have been observed in individuals with ASL-related conditions (PMID: 24166829, 28251416), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. -
Uncertain significance, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Nov 08, 2021	NM_001024943.1(ASL):c.437G>A(R146Q) is a missense variant classified as a variant of uncertain significance in the context of argininosuccinic aciduria. R146Q has been observed in cases with relevant disease (PMID: 28251416). Functional assessments of this variant are not available in the literature. R146Q has not been observed in population frequency databases. In summary, there is insufficient evidence to classify NM_001024943.1(ASL):c.437G>A(R146Q) as pathogenic or benign. Please note: this variant was assessed in the context of healthy population screening. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 21, 2024	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Jun 17, 2020	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.25

BayesDel_addAF

Pathogenic

0.44

BayesDel_noAF

Pathogenic

0.40

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.93

D;.;D;D;.

Eigen

Uncertain

0.35

Eigen_PC

Uncertain

0.33

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.96

.;D;D;D;D

M_CAP

Pathogenic

0.95

MetaRNN

Pathogenic

0.85

D;D;D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Benign

0.91

L;L;L;.;L

MutationTaster

Benign

1.0

D;D;D;D

PrimateAI

Uncertain

0.56

PROVEAN

Uncertain

-3.9

D;D;D;D;D

REVEL

Pathogenic

0.84

Sift

Benign

0.19

T;T;T;T;T

Sift4G

Benign

0.28

T;T;T;T;T

Polyphen

1.0

D;.;D;.;.

Vest4

0.78

MutPred

0.67

Loss of methylation at R146 (P = 0.1572);Loss of methylation at R146 (P = 0.1572);Loss of methylation at R146 (P = 0.1572);.;Loss of methylation at R146 (P = 0.1572);

MVP

0.97

MPC

1.0

ClinPred

0.99

GERP RS

4.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.8

Varity_R

0.83

gMVP

0.90

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over