chr7-66086764-G-A

Position:

chr7-66086764-G-A

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PP3_StrongPP5_Very_Strong

The NM_000048.4(ASL):c.545G>A(p.Arg182Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000337 in 1,603,044 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 Likely pathogenic (★★).

Frequency

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

Exomes 𝑓: 0.000037 ( 0 hom. )

Consequence

ASL
NM_000048.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8

Conservation

PhyloP100: 8.81

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 Pathogenic. Variant got 16 ACMG points.

PM1

In a helix (size 25) in uniprot entity ARLY_HUMAN there are 7 pathogenic changes around while only 0 benign (100%) in NM_000048.4

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.977

PP5

Variant 7-66086764-G-A is Pathogenic according to our data. Variant chr7-66086764-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 203613.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-66086764-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
ASL	NM_000048.4 linkuse as main transcript	c.545G>A	p.Arg182Gln	missense_variant	8/17	ENST00000304874.14	NP_000039.2
ASL	NM_001024943.2 linkuse as main transcript	c.545G>A	p.Arg182Gln	missense_variant	7/16		NP_001020114.1
ASL	NM_001024944.2 linkuse as main transcript	c.545G>A	p.Arg182Gln	missense_variant	7/15		NP_001020115.1
ASL	NM_001024946.2 linkuse as main transcript	c.524+102G>A		intron_variant			NP_001020117.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ASL	ENST00000304874.14 linkuse as main transcript	c.545G>A	p.Arg182Gln	missense_variant	8/17	1	NM_000048.4	ENSP00000307188	P1	P04424-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152144

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

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:

0.0000220

AC:

AN:

227286

Hom.:

AF XY:

0.0000405

AC XY:

AN XY:

123504

show subpopulations

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:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000493

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000365

AC:

AN:

1450900

Hom.:

Cov.:

AF XY:

0.0000444

AC XY:

AN XY:

721112

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000255

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000193

Gnomad4 NFE exome

AF:

0.0000461

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152144

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74320

show subpopulations

Gnomad4 AFR

AF:

0.0000241

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:

0.0000688

Hom.:

Bravo

AF:

0.0000189

ExAC

AF:

0.0000578

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Argininosuccinate lyase deficiency

Pathogenic:8

Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Centogene AG - the Rare Disease Company	-	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Feb 04, 2022	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Aug 24, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	Feb 16, 2023	PS3, PM3, PM2, PM1, PP3 -
Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 28, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 24, 2024	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 182 of the ASL protein (p.Arg182Gln). This variant is present in population databases (rs751590073, gnomAD 0.005%). This missense change has been observed in individual(s) with argininosuccinate lyase deficiency (PMID: 19703900, 24166829; Invitae; RQ355872). 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: 203613). 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%. Experimental studies have shown that this missense change affects ASL function (PMID: 19703900). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Knight Diagnostic Laboratories, Oregon Health and Sciences University	Dec 04, 2015	The c.545G>A (p.Arg182Gln) missense variant in the ASL gene has been previously reported in one affected individual with autosomal recessive Argininosuccinic aciduria. The affected individual harbored this missense variant in trans with a canonical splice site variant (IVS5+1G>A) reported to cause a premature protein truncation (Linnebank et al., 2002). Cultured fibroblast from this individual showed the enzyme activity of ASL was less than 2% relative to controls (Linnebank et al., 2002). The c.545G>A variant is located within a mutational hotspot which includes exons 5, 6, and 8 (Linnebank et al., 2002). Functional studies using a yeast complementation assay conclude the Arg182Gln variant is unable to complement relative to controls (Trevisson et al., 2009). The c.545G>A variant has been reported at low frequencies in the three control population databases (Exome Sequencing Project [ESP], 1000 Genomes, and ExAc) and multiple lines of computation evidence suggest a deleterious effect (GERP = 5.65; CADD = 34; polyPhen = 0.997; SIFT = 0). In addition, this variant has been reported as pathogenic in ClinVar by another clinical laboratory. Therefore, this collective evidence supports the classification of the c.545G>A (p.Arg182Gln) as a recessive Pathogenic variant for Argininosuccinic aciduria. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.29

BayesDel_addAF

Pathogenic

0.45

BayesDel_noAF

Pathogenic

0.55

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.91

D;D;D;.

Eigen

Pathogenic

0.87

Eigen_PC

Pathogenic

0.85

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.96

.;D;D;D

M_CAP

Pathogenic

0.97

MetaRNN

Pathogenic

0.98

D;D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.6

H;H;.;H

MutationTaster

Benign

1.0

D;D;D;D

PrimateAI

Uncertain

0.78

PROVEAN

Benign

-2.0

N;N;N;N

REVEL

Pathogenic

0.91

Sift

Benign

0.13

T;T;T;T

Sift4G

Uncertain

0.056

T;T;D;T

Polyphen

0.99

D;D;.;.

Vest4

0.96

MutPred

0.90

Loss of MoRF binding (P = 0.0241);Loss of MoRF binding (P = 0.0241);.;Loss of MoRF binding (P = 0.0241);

MVP

0.99

MPC

0.62

ClinPred

0.95

GERP RS

5.7

Varity_R

0.88

gMVP

0.97

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