rs121908642

chr9-130489404-C-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_054012.4(ASS1):c.910C>T(p.Arg304Trp) variant causes a missense change. The variant allele was found at a frequency of 0.0000167 in 1,613,940 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 Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R304Q) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000016 (0 hom.)
• Consequence: ASS1 NM_054012.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:8 O:1
• Conservation: PhyloP100: 3.62

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 Pathogenic. Variant got 18 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_054012.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr9-130489405-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 970822.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.954
• PP5: Variant 9-130489404-C-T is Pathogenic according to our data. Variant chr9-130489404-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 6330.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-130489404-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ASS1	NM_054012.4	c.910C>T	p.Arg304Trp	missense_variant	12/15	ENST00000352480.10
ASS1	NM_000050.4	c.910C>T	p.Arg304Trp	missense_variant	13/16

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ASS1	ENST00000352480.10	c.910C>T	p.Arg304Trp	missense_variant	12/15	1	NM_054012.4	P1

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152078 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000318 AC: 8 AN: 251460 Hom.: 0 AF XY: 0.0000368 AC XY: 5 AN XY: 135908

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000578

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: 0.0000352

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000164 AC: 24 AN: 1461862 Hom.: 0 Cov.: 33 AF XY: 0.0000179 AC XY: 13 AN XY: 727236

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000447

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000126

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000135

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152078 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74254

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000655

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000282 Hom.: 0

Bravo AF: 0.0000113

ExAC AF: 0.0000412 AC: 5

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Citrullinemia type I Pathogenic:5 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 12, 2020	Variant summary: ASS1 c.910C>T (p.Arg304Trp) results in a non-conservative amino acid change in the encoded protein sequence and it is predicted to involve in dimer-dimer interaction (Gao_2003). 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 3.2e-05 in 251460 control chromosomes (gnomAD). c.910C>T has been reported in the literature in multiple individuals affected with Citrullinemia Type I (Kobayashi_1995, Gao_2003). These data indicate that the variant is very likely to be associated with disease. At least one publication reports this variant results in significantly decreasing normal activity (Gao_2003). One ClinVar submitter (evaluation after 2014) cites the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Nov 01, 2022	This variant was identified as homozygous._x000D_ Criteria applied: PS3, PM3_STR, PM1, PM5, PM2_SUP, PP4 -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jul 05, 1990	- -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 22, 2020	- -

Citrullinemia Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	-	This variant has been previously reported as a compound heterozygous change in patients with Citrullinemia (PMID: 7977368, 12815590, 23246278, 28302489). Functional studies have shown that this missense variant affects normal function of ASS1 (PMID: 8792870). The c.910C>T (p.Arg304Trp) variant is present in the heterozygous state in the gnomAD population database at a frequency of 0.003% (9/282796) and thus is presumed to be rare. The c.910C>T (p.Arg304Trp) variant affects a weakly conserved amino acid and in silico tools predict a discordant effect on protein function. Based on the available evidence, the c.910C>T (p.Arg304Trp) variant is classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 05, 2024	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 304 of the ASS1 protein (p.Arg304Trp). This variant is present in population databases (rs121908642, gnomAD 0.009%). This missense change has been observed in individual(s) with citrullinemia (PMID: 7977368, 12815590, 23246278, 28302489). ClinVar contains an entry for this variant (Variation ID: 6330). 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: 8792870). For these reasons, this variant has been classified as Pathogenic. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Jul 14, 2014

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.76
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.46
Cadd	Uncertain	25
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	1.0	D;D;D
Eigen	Uncertain	0.60
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Uncertain	0.84	D
M_CAP	Pathogenic	0.42	D
MetaRNN	Pathogenic	0.95	D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.0	H;H;H
MutationTaster	Benign	1.0	A;A;A;A
PrimateAI	Uncertain	0.76	T
PROVEAN	Pathogenic	-6.7	D;D;D
REVEL	Pathogenic	0.92
Sift	Uncertain	0.014	D;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		0.87	P;P;P
Vest4		0.90
MVP		0.99
MPC		0.38
ClinPred		0.96	D
GERP RS		4.5
Varity_R		0.89
gMVP		0.82

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: rs121908642; hg19: chr9-133364791;