rs192838388

Positions:

chr9-130480398-G-A

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong

The NM_054012.4(ASS1):c.787G>A(p.Val263Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000892 in 1,614,204 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 0.000046 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000094 ( 0 hom. )

Consequence

ASS1
NM_054012.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:15O:1

Conservation

PhyloP100: 7.38

Variant links:

Genes affected

ASS1 (HGNC:758): (argininosuccinate synthase 1) The protein encoded by this gene catalyzes the penultimate step of the arginine biosynthetic pathway. There are approximately 10 to 14 copies of this gene including the pseudogenes scattered across the human genome, among which the one located on chromosome 9 appears to be the only functional gene for argininosuccinate synthetase. Mutations in the chromosome 9 copy of this gene cause citrullinemia. Two transcript variants encoding the same protein have been found for this gene. [provided by RefSeq, Aug 2012]

ASS1 links:

ASS1 (HGNC:):

ASS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.956

PP5

Variant 9-130480398-G-A is Pathogenic according to our data. Variant chr9-130480398-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 92372.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-130480398-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ASS1	NM_054012.4 linkuse as main transcript	c.787G>A	p.Val263Met	missense_variant	11/15	ENST00000352480.10	NP_446464.1	P00966Q5T6L4
ASS1	NM_000050.4 linkuse as main transcript	c.787G>A	p.Val263Met	missense_variant	12/16		NP_000041.2	P00966Q5T6L4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ASS1	ENST00000352480.10 linkuse as main transcript	c.787G>A	p.Val263Met	missense_variant	11/15	1	NM_054012.4	ENSP00000253004.6		P00966

Frequencies

GnomAD3 genomes

AF:

0.0000525

AC:

AN:

152244

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:

0.00316

Gnomad NFE

AF:

0.0000882

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.0000477

AC:

AN:

251362

Hom.:

AF XY:

0.0000294

AC XY:

AN XY:

135846

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.0000992

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.0000653

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000704

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000937

AC:

137

AN:

1461842

Hom.:

Cov.:

AF XY:

0.0000921

AC XY:

AN XY:

727208

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:

0.0000348

Gnomad4 FIN exome

AF:

0.0000375

Gnomad4 NFE exome

AF:

0.000110

Gnomad4 OTH exome

AF:

0.000132

GnomAD4 genome

AF:

0.0000459

AC:

AN:

152362

Hom.:

Cov.:

AF XY:

0.0000671

AC XY:

AN XY:

74508

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:

0.0000882

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.000121

Hom.:

Bravo

AF:

0.0000491

ExAC

AF:

0.0000494

AC:

EpiCase

AF:

0.000491

EpiControl

AF:

0.000119

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:15Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Citrullinemia type I

Pathogenic:11Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Nov 10, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 27, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Knight Diagnostic Laboratories, Oregon Health and Sciences University	Sep 09, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Centre for Inherited Metabolic Diseases, Karolinska University Hospital	Jul 23, 2024	The variant is frequently reported as pathogenic in various databases such as HGMD and Clinvar (PS1). The variant was observed in trans with a pathogenic variant (PM3). The clinical test in combination with phenotye allows for use of PP4 - strong (based on Biesecker et al. 2024 ClinGen guidance for use of the PP1/BS4 co-segregation and PP4 phenotype specificity criteria, PMID: 38103548) -
Pathogenic, criteria provided, single submitter	curation	Laboratory of Medical Genetics, National & Kapodistrian University of Athens	Feb 01, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 02, 2020	Variant summary: ASS1 c.787G>A (p.Val263Met) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4.8e-05 in 251362 control chromosomes (gnomAD). This frequency is not higher than expected for a pathogenic variant in ASS1 causing Citrullinemia Type I (4.8e-05 vs 0.0041), allowing no conclusion about variant significance. c.787G>A has been reported in the literature in multiple individuals in compound heterozygous or homozygous state affected with mild citrullinemia (Haberie_2003, Dimmock_2008, Barends_2014, Diez-Fernandez_2017). These data indicate that the variant is very likely to be associated with disease. At least one in vitro functional study reports this variant had an impact on protein function and results in 36% of normal activity. Six Four ClinVar submitters (evaluation after 2014) cite the variant as pathogenic (4x) and likely pathogenic (2x). Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 21, 2023	The p.Val263Met (NM_000050.4 c.787G>A) variant in ASS1 has been reported in at least 6 compound heterozygous and 6 homozygous individuals with mild citrullinemia and segregated in 2 siblings from two families (Haeberle 2003 PMID: 14680976, Diez-Fernandez 2017 PMID: 28111830). Some of these individuals were asymptomatic despite having mild hypercitrullinaemia (Haeberle 2003 PMID: 14680976, Diez-Fernandez 2017 PMID: 28111830). It has been identified in 0.01% (1/10148) of Ashkenazi Jewish chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs192838388), and ] has also been reported in ClinVar (Variation ID#92372) as pathogenic by several clinical laboratories. This variant led to reduced enzyme activity (36% as compared to wild-type) in in vitro studies (Berning 2008 PMID: 18473344). In addition, computational prediction tools suggest that the variant may impact the protein. In summary, the p.Val263Met variant meets criteria to be classified as pathogenic for citrullinemia in an autosomal recessive manner, though it is associated with a milder phenotype. ACMG/AMP Criteria applied: PM3_VeryStrong, PP1_Moderate, PS3_Supporting, PM2_Supporting, PP3. -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Dec 13, 2022	- -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Jun 01, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Aug 28, 2019	A heterozygous missense variant, NM_000050.4(ASS1):c.787G>A, has been identified in exon 12 of 16 of the ASS1 gene. The variant is predicted to result in a minor amino acid change from valine to methionine at position 263 of the protein (NP_000041.2(ASS1):p.(Val263Met)). The valine residue at this position has high conservation (100 vertebrates, UCSC), and is located within the Arginosuccinate synthase domain. In silico predictions for this variant are consistently pathogenic (Polyphen, SIFT, CADD, Mutation Taster). The variant is present in the gnomAD database at a frequency of 0.005% (15 heterozygotes, 0 homozygotes). The variant has been previously described as pathogenic and segregated with disease in multiple families with citrullinemia (ClinVar, Häberle, J. et al. (2003), Berning, C. et al. (2008), Glamuzina, E. et al. (2011), Diez-Fernandez, C. et al. (2017)). Additionally, in vitro studies demonstrated a reduced enzyme activity in p.V263M (Berning, C. et al. (2008)). Based on the information available at the time of curation, this variant has been classified as PATHOGENIC. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Jun 16, 2017	V263M may be associated with a mild form of citrullinemia type 1. -
not provided, no classification provided	literature only	GeneReviews	-	- -

not provided

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 03, 2012	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 02, 2022	Published functional studies demonstrate a damaging effect, V263M mutant protein expressed in E.coli yielded 30% residual enzymatic activity (PMID: 18473344); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 23757202, 21244552, 34598035, 14680976, 20690080, 26589311, 28111830, 30609409, 34426522, 31589614, 32778825, 31469252, 35726796, 35267200, 25433810, 20301631, 25047749, 23780642, 22473243, 12684898, 31208364, 18473344, 18925679) -

Citrullinemia

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 27, 2024

This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 263 of the ASS1 protein (p.Val263Met). This variant is present in population databases (rs192838388, gnomAD 0.01%). This missense change has been observed in individuals with Citrullinemia type I (PMID: 4680976, 18473344, 18925679, 23780642). ClinVar contains an entry for this variant (Variation ID: 92372). 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 ASS1 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects ASS1 function (PMID: 18473344). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.70

BayesDel_addAF

Pathogenic

0.42

BayesDel_noAF

Pathogenic

0.55

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.99

D;D;D

Eigen

Pathogenic

0.73

Eigen_PC

Uncertain

0.62

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.90

.;.;D

M_CAP

Pathogenic

0.70

MetaRNN

Pathogenic

0.96

D;D;D

MetaSVM

Pathogenic

1.0

MutationAssessor

Pathogenic

3.9

H;H;H

PrimateAI

Uncertain

0.71

PROVEAN

Uncertain

-2.4

N;N;N

REVEL

Pathogenic

0.93

Sift

Uncertain

0.0010

D;D;D

Sift4G

Pathogenic

0.0010

D;D;D

Polyphen

1.0

D;D;D

Vest4

0.87

MVP

0.97

MPC

0.92

ClinPred

0.93

GERP RS

4.7

Varity_R

0.93

gMVP

0.92

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