rs138279074

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 3P and 1B. PM1PP2BP4

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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R100C) has been classified 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

Publications

3 publications found

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 Gene-Disease associations (from GenCC):

citrullinemia type I
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, Myriad Women’s Health, G2P
acute neonatal citrullinemia type I
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
adult-onset citrullinemia type I
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ASS1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 5 uncertain in NM_054012.4

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 49 curated pathogenic missense variants (we use a threshold of 10). The gene has 4 curated benign missense variants. Gene score misZ: 0.75759 (below the threshold of 3.09). Trascript score misZ: 1.8061 (below the threshold of 3.09). GenCC associations: The gene is linked to citrullinemia type I, adult-onset citrullinemia type I, acute neonatal citrullinemia type I.

BP4

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_054012.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ASS1	NM_054012.4	MANE Select	c.299G>A	p.Arg100His	missense	Exon 4 of 15	NP_446464.1
	ASS1	NM_000050.4		c.299G>A	p.Arg100His	missense	Exon 5 of 16	NP_000041.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
ASS1	ENST00000352480.10	TSL:1 MANE Select	c.299G>A	p.Arg100His	missense	Exon 4 of 15	ENSP00000253004.6
ASS1	ENST00000372393.7	TSL:5	c.299G>A	p.Arg100His	missense	Exon 5 of 16	ENSP00000361469.2
ASS1	ENST00000372394.5	TSL:2	c.299G>A	p.Arg100His	missense	Exon 5 of 16	ENSP00000361471.1

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

GnomAD2 exomes

AF:

0.000180

AC:

AN:

250286

AF XY:

0.000185

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 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

African (AFR)

AF:

0.0000598

AC:

AN:

33450

American (AMR)

AF:

0.000492

AC:

AN:

44708

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26132

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39698

South Asian (SAS)

AF:

0.000406

AC:

AN:

86208

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53316

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5234

European-Non Finnish (NFE)

AF:

0.000139

AC:

154

AN:

1111840

Other (OTH)

AF:

0.000216

AC:

AN:

60314

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.467

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000184

AC:

AN:

152308

Hom.:

Cov.:

AF XY:

0.000215

AC XY:

AN XY:

74472

show subpopulations

African (AFR)

AF:

0.0000962

AC:

AN:

41580

American (AMR)

AF:

0.000784

AC:

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5162

South Asian (SAS)

AF:

0.000207

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000132

AC:

AN:

68026

Other (OTH)

AF:

0.000945

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000177

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

Oct 02, 2017

Counsyl

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com.

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Sep 16, 2020

Natera, Inc.

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

Jul 05, 2017

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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.

not provided

Uncertain:2

May 02, 2017

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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.

Sep 05, 2025

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Reported in an individuals with elevated citrulline who was also heterozygous for additional variants in ASS1 (PMID: 28111830); 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, 37443404, 28111830)

not specified

Uncertain:1

Oct 14, 2024

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

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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.

Inborn genetic diseases

Uncertain:1

Nov 04, 2021

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

(Bijarnia-Mahay, 2018) Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.

Citrullinemia

Uncertain:1

Oct 13, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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.

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Uncertain

0.11

BayesDel_noAF

Pathogenic

0.23

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.97

Eigen

Benign

0.17

Eigen_PC

Uncertain

0.27

FATHMM_MKL

Uncertain

0.83

LIST_S2

Uncertain

0.88

M_CAP

Uncertain

0.092

MetaRNN

Benign

0.35

MetaSVM

Pathogenic

0.95

MutationAssessor

Uncertain

2.8

PhyloP100

4.0

PrimateAI

Uncertain

0.70

PROVEAN

Uncertain

-3.0

REVEL

Pathogenic

0.71

Sift

Uncertain

0.0080

Sift4G

Uncertain

0.037

Polyphen

0.11

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

Mutation Taster

=3/97

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over