chr9-130458525-G-A

Position:

chr9-130458525-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_054012.4(ASS1):c.299G>A(p.Arg100His) variant causes a missense change. The variant allele was found at a frequency of 0.000158 in 1,613,208 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00018 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00016 ( 0 hom. )

Consequence

ASS1
NM_054012.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:9

Conservation

PhyloP100: 3.98

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 Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.34552276).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ASS1	NM_054012.4 linkuse as main transcript	c.299G>A	p.Arg100His	missense_variant	4/15	ENST00000352480.10	NP_446464.1	P00966Q5T6L4
ASS1	NM_000050.4 linkuse as main transcript	c.299G>A	p.Arg100His	missense_variant	5/16		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.299G>A	p.Arg100His	missense_variant	4/15	1	NM_054012.4	ENSP00000253004.6		P00966

Frequencies

GnomAD3 genomes

AF:

0.000184

AC:

AN:

152192

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000965

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000785

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000132

Gnomad OTH

AF:

0.000955

GnomAD3 exomes

AF:

0.000180

AC:

AN:

250286

Hom.:

AF XY:

0.000185

AC XY:

AN XY:

135496

show subpopulations

Gnomad AFR exome

AF:

0.000124

Gnomad AMR exome

AF:

0.000405

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000142

Gnomad OTH exome

AF:

0.000491

GnomAD4 exome

AF:

0.000155

AC:

227

AN:

1460900

Hom.:

Cov.:

AF XY:

0.000162

AC XY:

118

AN XY:

726744

show subpopulations

Gnomad4 AFR exome

AF:

0.0000598

Gnomad4 AMR exome

AF:

0.000492

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.000406

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000139

Gnomad4 OTH exome

AF:

0.000216

GnomAD4 genome

AF:

0.000184

AC:

AN:

152308

Hom.:

Cov.:

AF XY:

0.000215

AC XY:

AN XY:

74472

show subpopulations

Gnomad4 AFR

AF:

0.0000962

Gnomad4 AMR

AF:

0.000784

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000132

Gnomad4 OTH

AF:

0.000945

Alfa

AF:

0.000214

Hom.:

Bravo

AF:

0.000291

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.000165

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.000109

EpiControl

AF:

0.000178

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Citrullinemia type I

Uncertain:4

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jul 05, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Oct 02, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 31, 2018	- -

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Mar 30, 2023	Reported in an individual with cholestasis, failure to thrive, and mildly elevated citrulline who was also heterozygous for another variant in ASS1 (Diez-Fernandez et al., 2017); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 30285816, 34426522, 31469252, 28111830) -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	May 02, 2017	The p.Arg100His variant (rs138279074) has not been reported in the medical literature, nor is it listed in gene-specific variant databases. It is listed in the Genome Aggregation Database (gnomAD) browser with an overall frequency of 0.017% (identified in 46 out of 276,470 chromosomes). The arginine at codon 100 is moderately conserved considering 12 species (Alamut software v2.8.1), and computational analyses suggest this variant does not have a significant effect on ASS1 protein structure/function (SIFT: tolerated and PolyPhen2: benign). However, based on the available information, the clinical significance of the p.Arg100His variant cannot be determined with certainty. -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Oct 14, 2024

Variant summary: ASS1 c.299G>A (p.Arg100His) results in a non-conservative amino acid change located in the Arginosuccinate synthase-like, N-terminal domain (IPR048267) of 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 0.00018 in 250286 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in ASS1 causing Citrullinemia Type I (0.00018 vs 0.0041), allowing no conclusion about variant significance. c.299G>A has been reported in the literature in individuals affected with Citrullinemia Type I (Diez-Fernandez_2017, Bijarnia-Mahay_2018, Zielonka_2019, Shum_2023). These data indicate that the variant may be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function using a biallelic expression system where the variant was expressed together with a pathogenic variant (Zielonka_2019), however, this does not allow convincing conclusions about the variant effect in isolation. The following publications have been ascertained in the context of this evaluation (PMID: 28111830, 30285816, 31469252, 37443404). ClinVar contains an entry for this variant (Variation ID: 439417). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. -

Citrullinemia

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 13, 2022

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 100 of the ASS1 protein (p.Arg100His). This variant is present in population databases (rs138279074, gnomAD 0.04%). This missense change has been observed in individual(s) with citrullinemia type 1 (PMID: 28111830, 30285816, 31469252). ClinVar contains an entry for this variant (Variation ID: 439417). 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 not expected to disrupt ASS1 protein function. This variant disrupts the p.Arg100 amino acid residue in ASS1. Other variant(s) that disrupt this residue have been observed in individuals with ASS1-related conditions (PMID: 28111830), which suggests that this may be a clinically significant amino acid residue. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 04, 2021

(Bijarnia-Mahay, 2018) 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

Benign

0.15

BayesDel_addAF

Uncertain

0.11

BayesDel_noAF

Pathogenic

0.23

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.97

D;D;D;.;.

Eigen

Benign

0.17

Eigen_PC

Uncertain

0.27

FATHMM_MKL

Uncertain

0.83

LIST_S2

Uncertain

0.88

.;.;D;D;D

M_CAP

Uncertain

0.092

MetaRNN

Benign

0.35

T;T;T;T;T

MetaSVM

Pathogenic

0.95

MutationAssessor

Uncertain

2.8

M;M;M;.;.

PrimateAI

Uncertain

0.70

PROVEAN

Uncertain

-3.0

D;D;D;D;D

REVEL

Pathogenic

0.71

Sift

Uncertain

0.0080

D;D;D;T;T

Sift4G

Uncertain

0.037

D;D;D;D;T

Polyphen

0.11

B;B;B;.;.

Vest4

0.47

MVP

0.98

MPC

0.33

ClinPred

0.074

GERP RS

4.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.6

Varity_R

0.30

gMVP

0.70

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