rs121908644

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM1PM2PM5PP3PP5_Very_Strong

The NM_054012.4(ASS1):c.256C>T(p.Arg86Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000403 in 1,612,422 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. R86H) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000043 ( 0 hom. )

Consequence

ASS1
NM_054012.4 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:7

Conservation

PhyloP100: 4.06

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 15 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, 4 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 chr9-130458483-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 265960.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.807

PP5

Variant 9-130458482-C-T is Pathogenic according to our data. Variant chr9-130458482-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 6332.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-130458482-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ASS1	NM_054012.4 linkuse as main transcript	c.256C>T	p.Arg86Cys	missense_variant	4/15	ENST00000352480.10
ASS1	NM_000050.4 linkuse as main transcript	c.256C>T	p.Arg86Cys	missense_variant	5/16

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ASS1	ENST00000352480.10 linkuse as main transcript	c.256C>T	p.Arg86Cys	missense_variant	4/15	1	NM_054012.4	P1

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152170

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:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000438

AC:

AN:

250884

Hom.:

AF XY:

0.0000516

AC XY:

AN XY:

135676

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000202

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000353

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000431

AC:

AN:

1460252

Hom.:

Cov.:

AF XY:

0.0000344

AC XY:

AN XY:

726454

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.000157

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000375

Gnomad4 NFE exome

AF:

0.0000441

Gnomad4 OTH exome

AF:

0.0000664

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152170

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74340

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:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000665

Hom.:

Bravo

AF:

0.0000453

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000412

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Citrullinemia type I

Pathogenic:4

Pathogenic, no assertion criteria provided	literature only	OMIM	Feb 01, 1991	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	-	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Counsyl	Jun 27, 2017	- -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 15, 2020	- -

Citrullinemia

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 07, 2023	Variant summary: ASS1 c.256C>T (p.Arg86Cys) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4.4e-05 in 250884 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in ASS1 causing Citrullinemia Type I (4.4e-05 vs 0.0041), allowing no conclusion about variant significance. c.256C>T has been reported in the literature in multiple homozygous patients (Martin-Hernandez_2014, Zielonka_2019), and in at least one compound heterozygous individual in trans from a pathogenic variant (Kobayashi_1991), with Citrullinemia Type I and associated phenotypes. These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function showing residual enzymatic ASS1 activity in a homozygous indivdual was about 5% of wildtype (Zielonka_2019) . Four 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 (n=3) and likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 30, 2024	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 86 of the ASS1 protein (p.Arg86Cys). This variant is present in population databases (rs121908644, gnomAD 0.02%). This missense change has been observed in individual(s) with citrullinemia type 1 (PMID: 1943692, 25433810). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 6332). 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 with a negative predictive value of 80%. Experimental studies have shown that this missense change affects ASS1 function (PMID: 1943692). This variant disrupts the p.Arg86 amino acid residue in ASS1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 12815590). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

May 17, 2023

Published functional studies demonstrate a damaging effect as residual enzymatic activity was reduced to about 20% of wild-type (Zielonka et al., 2019); 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: 24772957, 24508627, 22494545, 12815590, 1943692, 25433810, 19006241, 7977368, 28111830, 31589614, 32778825, 31469252) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.53

BayesDel_addAF

Pathogenic

0.27

BayesDel_noAF

Pathogenic

0.43

Cadd

Pathogenic

Dann

Uncertain

1.0

DEOGEN2

Pathogenic

0.96

D;D;D;.;.

Eigen

Uncertain

0.29

Eigen_PC

Uncertain

0.36

FATHMM_MKL

Uncertain

0.86

M_CAP

Uncertain

0.095

MetaRNN

Pathogenic

0.81

D;D;D;D;D

MetaSVM

Pathogenic

0.90

MutationAssessor

Uncertain

2.9

M;M;M;.;.

MutationTaster

Benign

1.0

A;A;A;A

PrimateAI

Pathogenic

0.81

PROVEAN

Pathogenic

-6.2

D;D;D;D;D

REVEL

Pathogenic

0.83

Sift

Benign

0.059

T;T;T;T;T

Sift4G

Benign

0.14

T;T;T;T;T

Polyphen

0.24

B;B;B;.;.

Vest4

0.95

MVP

0.97

MPC

0.43

ClinPred

0.60

GERP RS

4.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.75

gMVP

0.83

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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