rs121908639

Positions:

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM2PM5PP3_StrongPP5_Very_Strong

The NM_054012.4(ASS1):c.970G>A(p.Gly324Ser) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000514 in 1,613,900 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 15/27 in silico tools predict a damaging outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G324V) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000054 ( 0 hom. )

Consequence

ASS1
NM_054012.4 missense, splice_region

Scores

Splicing: ADA: 1.000

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:13

Conservation

PhyloP100: 9.28

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 16 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr9-130494867-G-T is described in Lovd as [Pathogenic].

PP3

Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

PP5

Variant 9-130489464-G-A is Pathogenic according to our data. Variant chr9-130489464-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 6327.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-130489464-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.970G>A	p.Gly324Ser	missense_variant, splice_region_variant	12/15	ENST00000352480.10	NP_446464.1
ASS1	NM_000050.4 linkuse as main transcript	c.970G>A	p.Gly324Ser	missense_variant, splice_region_variant	13/16		NP_000041.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ASS1	ENST00000352480.10 linkuse as main transcript	c.970G>A	p.Gly324Ser	missense_variant, splice_region_variant	12/15	1	NM_054012.4	ENSP00000253004	P1

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152076

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:

0.0000588

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000358

AC:

AN:

251184

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135866

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000145

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000540

AC:

AN:

1461824

Hom.:

Cov.:

AF XY:

0.0000523

AC XY:

AN XY:

727218

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000134

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000126

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000567

Gnomad4 OTH exome

AF:

0.0000662

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152076

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74302

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:

0.0000588

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000244

Hom.:

Bravo

AF:

0.0000302

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ExAC

AF:

0.0000494

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:13

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Citrullinemia type I

Pathogenic:9

Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Jan 20, 2021	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jan 17, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 25, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Centre de Genetique Humaine, Institut de Pathologie et de Genetique	Dec 21, 2023	The c.970G>A impacts a highly conserved nucleotide (phyloP: 9.18) and a highly conserved amino acid (down to the yeast). It has 2 occurrences in gnomAD v4. Prediction tools pedict a deleterious effect (20/21), CADD : 34, REVEL 0.970. It is predicted to alter splicing (SpliceAI : donor loss 0.67). In vitro data revealed complete loss of enzyme activity (residual activity <2%) (PMID: 18473344). Despite having a severe impact on enzyme activity in vitro, the variant was reported in two asymptomatic patients with citrullinemia type 1, one was hmozygote for the variant and the second was compound heterozygote with the c.40G>A p.(Gly14Ser) variant (PMID: 14680976). It was also reported in a Korean cohort with neonatal onset (1 to 16d, in trans with c.421-2A>G) or later onset (3m, in trans with c.421-2A>G or c.1128-6_1188dup67) (PMID: 23246278). Our patient (mild form of ASSD) carries the c.808G>C variant in cis with c.206T>C, inherited from his father, and in trans with c.970G>A, inherited from his mother. Intriguingly, the paternal allele of our patient is composed of the two variants reported in PMID: 11708871, which are presumably in trans in the published patient (severe case). There is second published patient who also carries the same two variants with no reported segregation (PMID: 12815590). In gnomAD, c.206T>C and c.808G>C have the same number of occurrences (v2.1.1 : 2-2, v4.0.0 : 5-5). These two variant might be on the same haplotype and we postulate that there is a third variant in trans that was not found in the first published case (PMID: 11708871). This would explain why our patient has a mild phenotype resulting from an hypomorphic allele c.970G>A (PMID: 14680976) + a severe allele [c.206T>C;c.808G>C]. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Apr 04, 2013	- -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	Oct 02, 2021	Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000006327.8, PS1). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.0000358, PM2). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least one similarly affected unrelated individual (PMID:16475226, 12815590 PM3). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.97, 3Cnet: 0.990, PP3). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Apr 18, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Centre for Mendelian Genomics, University Medical Centre Ljubljana	Jan 31, 2019	This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PM2,PM3,PP3,PP4. -
Likely pathogenic, criteria provided, single submitter	literature only	Counsyl	Jul 19, 2014	- -

Citrullinemia

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 01, 2022	Variant summary: ASS1 c.970G>A (p.Gly324Ser) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3.6e-05 in 251184 control chromosomes. c.970G>A has been reported in the literature in numerous individuals affected with Citrullinemia Type I, in the homozygous and compound heterozygous state (examples: Gao_2003, Haberle_2003, Lee_2013, etc). These data indicate that the variant is very likely to be associated with disease. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 16, 2024	This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 324 of the ASS1 protein (p.Gly324Ser). This variant also falls at the last nucleotide of exon 13, which is part of the consensus splice site for this exon. This variant is present in population databases (rs121908639, gnomAD 0.01%). This missense change has been observed in individual(s) with citrullinemia (PMID: 2358466, 11211875, 12815590, 14680976, 18473344). ClinVar contains an entry for this variant (Variation ID: 6327). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). For these reasons, this variant has been classified as Pathogenic. -

ASS1-related disorder

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 02, 2023

The ASS1 c.970G>A variant is predicted to result in the amino acid substitution p.Gly324Ser. This variant has been reported in the homozygous state or heterozygous state with a second causative ASS1 variant in multiple individuals with citrullinaemia type I; in at least one patient, it was found in trans with a pathogenic variant (Kobayashi et al. 1990. PubMed ID: 2358466; Hong et al. 2000. PubMed ID: 10987146; Gao et al. 2003. PubMed ID: 12815590; Häberle et al. 2003. PubMed ID: 14680976; Bijarnia-Mahay et al. 2018. PubMed ID: 30285816). In one study of a group of patients with classic citrullinemia, it was found on 4 of 45 independent alleles, though additional genetic information was not provided on those patients (Berning et al. 2008. PubMed ID: 18473344). In an E. coli expression study, the p.Gly324Ser substitution reduced enzyme activity to <2% (Berning et al. 2008. PubMed ID: 18473344). Additionally, the c.970G nucleotide is the last nucleotide in exon 13 of the ASS1 gene, and the c.970G>A variant is predicted to impact splicing at the adjacent canonical splice donor site (SpliceAI, Jaganathan et al. 2019. PubMed ID: 30661751). This variant is reported in 0.014% of alleles in individuals of Latino descent in gnomAD. In summary, this variant is interpreted as pathogenic. -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Jul 01, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.94

BayesDel_addAF

Pathogenic

0.40

BayesDel_noAF

Pathogenic

0.59

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

1.0

D;D;D

Eigen

Pathogenic

0.83

Eigen_PC

Uncertain

0.63

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.90

.;.;D

M_CAP

Pathogenic

0.68

MetaRNN

Pathogenic

1.0

D;D;D

MetaSVM

Pathogenic

0.88

MutationAssessor

Pathogenic

4.4

H;H;H

MutationTaster

Benign

1.0

A;A;A;A

PrimateAI

Pathogenic

0.84

PROVEAN

Pathogenic

-5.9

D;D;D

REVEL

Pathogenic

0.97

Sift

Pathogenic

0.0

D;D;D

Sift4G

Uncertain

0.0020

D;D;D

Polyphen

1.0

D;D;D

Vest4

0.94

MutPred

0.99

Loss of stability (P = 0.1598);Loss of stability (P = 0.1598);Loss of stability (P = 0.1598);

MVP

0.98

MPC

0.90

ClinPred

1.0

GERP RS

4.5

Varity_R

0.95

gMVP

0.92

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

1.0

SpliceAI score (max)

0.67

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.21

Position offset: 4

DS_DL_spliceai

0.67

Position offset: 0

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