rs138279074

chr9-130458525-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

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
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:9
• Conservation: PhyloP100: 3.98

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]

ACMG classification

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	UniProt
ASS1	NM_054012.4	c.299G>A	p.Arg100His	missense_variant	4/15	ENST00000352480.10
ASS1	NM_000050.4	c.299G>A	p.Arg100His	missense_variant	5/16

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ASS1	ENST00000352480.10	c.299G>A	p.Arg100His	missense_variant	4/15	1	NM_054012.4	P1

Frequencies

GnomAD3 genomes AF: 0.000184 AC: 28 AN: 152192 Hom.: 0 Cov.: 33

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: 45 AN: 250286 Hom.: 0 AF XY: 0.000185 AC XY: 25 AN XY: 135496

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.: 0 Cov.: 32 AF XY: 0.000162 AC XY: 118 AN XY: 726744

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: 28 AN: 152308 Hom.: 0 Cov.: 33 AF XY: 0.000215 AC XY: 16 AN XY: 74472

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.: 0

Bravo AF: 0.000291

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000165 AC: 20

Asia WGS AF: 0.000289 AC: 1 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

Submissions by phenotype

Citrullinemia type I Uncertain:4

Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 31, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Oct 02, 2017	- -
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. -

not provided Uncertain:2

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. -
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) -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Mar 21, 2023

Variant summary: ASS1 c.299G>A (p.Arg100His) results in a non-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 0.00018 in 250286 control chromosomes (gnomAD). This frequency is not higher than the estimated maximum expected for a pathogenic variant in ASS1 causing Citrullinemia Type I (0.0041), allowing no conclusion about variant significance. c.299G>A has been reported in the literature in at least two compound heterozygous individuals affected with Citrullinemia Type I (Diez-Fernandez_2017, Bijarnia-Mahay_2018, Zielonka_2019), one of these individuals carried a pathogenic variant in trans in trans (Zielonka_2019), however the severity of the disease was not specified for this individual. Authors of this report also performed in vitro functional studies, and demonstrated about 60% residual enzymatic activity, using a biallelic expression system, where these variants were expressed together. Since the presence of the other allele in itself can explain the ~60% residual activity, this result does not allow convincing conclusions about the variant effect. These data therefore do not provide unequivocal conclusions about association of the variant with Citrullinemia Type I. Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014, and all laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. -

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. -

Citrullinemia Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Pathogenic	0.23
Cadd	Pathogenic	26
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	D
M_CAP	Uncertain	0.092	D
MetaRNN	Benign	0.35	T;T;T;T;T
MetaSVM	Pathogenic	0.95	D
MutationAssessor	Uncertain	2.8	M;M;M;.;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.70	T
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	T
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

Other links and lift over

dbSNP: rs138279074; hg19: chr9-133333912;