chr9-130489423-A-G

Position:

chr9-130489423-A-G

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1PM2PM5PP3_ModeratePP5

The NM_054012.4(ASS1):c.929A>G(p.Lys310Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000173 in 1,613,984 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K310Q) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000018 ( 0 hom. )

Consequence

ASS1
NM_054012.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:5U:2

Conservation

PhyloP100: 8.72

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 Likely_pathogenic. Variant got 9 ACMG points.

PM1

In a helix (size 19) in uniprot entity ASSY_HUMAN there are 8 pathogenic changes around while only 0 benign (100%) 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 chr9-130489422-A-C is described in Lovd as [Pathogenic].

PP3

MetaRNN computational evidence supports a deleterious effect, 0.906

PP5

Variant 9-130489423-A-G is Pathogenic according to our data. Variant chr9-130489423-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 365260.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=4, Uncertain_significance=2, Pathogenic=1}. Variant chr9-130489423-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ASS1	NM_054012.4 linkuse as main transcript	c.929A>G	p.Lys310Arg	missense_variant	12/15	ENST00000352480.10	NP_446464.1
ASS1	NM_000050.4 linkuse as main transcript	c.929A>G	p.Lys310Arg	missense_variant	13/16		NP_000041.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ASS1	ENST00000352480.10 linkuse as main transcript	c.929A>G	p.Lys310Arg	missense_variant	12/15	1	NM_054012.4	ENSP00000253004	P1

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152108

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000278

AC:

AN:

251470

Hom.:

AF XY:

0.0000294

AC XY:

AN XY:

135910

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

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:

0.0000527

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000178

AC:

AN:

1461876

Hom.:

Cov.:

AF XY:

0.0000124

AC XY:

AN XY:

727242

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000216

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152108

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74306

show subpopulations

Gnomad4 AFR

AF:

0.0000242

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:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000111

Hom.:

Bravo

AF:

0.0000151

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.00000824

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:5Uncertain:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Citrullinemia type I

Pathogenic:2Uncertain:1

Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jun 09, 2019	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Feb 28, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	May 04, 2018	The ASS1 c.929A>G (p.Lys310Arg) variant is a missense variant that has been reported in a compound heterozygous state in at least one individual with citrullinemia type I (Enns et al. 2005; Gao et al. 2003). Control data are unavailable for this variant, which is reported at a frequency of 0.00012 in the European American population of the Exome Sequencing Project. This frequency is based on only one allele in a region of good sequencing coverage, so the variant is presumed to be rare. The evidence for this variant is limited. The p.Lys310Arg variant is therefore classified as a variant of unknown significance but suspicious for pathogenicity for citrullinemia. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

not specified

Pathogenic:1Uncertain:1

Likely pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Mar 21, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 09, 2023	Variant summary: ASS1 c.929A>G (p.Lys310Arg) results in a 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 2.8e-05 in 251470 control chromosomes (gnomAD). c.929A>G has been reported in the literature in at-least one individual affected with Citrullinemia Type I (example: Gao_2003 and Enns_2005). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. A different variant affecting this residue (c.928A>C p.K310Q) have been reported in an individual affected with Citrullinemia (Gao_2003), suggesting this residue may be critical for normal protein function. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as VUS (n=1) and pathogenic/likely pathogenic (n=4). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. -

Citrullinemia

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jun 05, 2023

For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Lys310 amino acid residue in ASS1. Other variant(s) that disrupt this residue have been observed in individuals with ASS1-related conditions (PMID: 15266621), which suggests that this may be a clinically significant amino acid residue. 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. ClinVar contains an entry for this variant (Variation ID: 365260). This missense change has been observed in individual(s) with clinical features of ASS1-related conditions (PMID: 12815590, 15863597; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is present in population databases (rs199751308, gnomAD 0.004%). This sequence change replaces lysine, which is basic and polar, with arginine, which is basic and polar, at codon 310 of the ASS1 protein (p.Lys310Arg). -

not provided

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Aug 31, 2016

The K310R variant in the ASS1 gene has been reported in a patient with adult/late-onset classic citrullinemia who had no detectable arginosuccinate synthetase activity in fibroblasts and who also harbored a pathogenic frameshift variant in the ASS1 gene (Gao et al. 2003). The K310R variant was not observed with any significant frequency in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project. This substitution occurs at a position that is conserved across species. Furthermore, K310 is located within the catalytic domain of the argininosuccinate synthetase enzyme and is believed to be involved with dimer interaction, and another missense variant at the same position (K310Q) has been identified in a patient with no detectable argininosuccinate synthetase activity who also harbored a splice site variant in the ASS1 gene (Gao et al. 2003). In summary, we interpret K310R to be likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Pathogenic

0.41

BayesDel_noAF

Pathogenic

0.48

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.76

D;D;D

Eigen

Uncertain

0.54

Eigen_PC

Uncertain

0.53

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.96

.;.;D

M_CAP

Pathogenic

0.45

MetaRNN

Pathogenic

0.91

D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Benign

1.7

L;L;L

MutationTaster

Benign

1.0

D;D;D;D

PrimateAI

Pathogenic

0.80

PROVEAN

Benign

-0.93

N;N;N

REVEL

Pathogenic

0.82

Sift

Benign

1.0

T;T;T

Sift4G

Benign

1.0

T;T;T

Polyphen

0.99

D;D;D

Vest4

0.95

MVP

0.97

MPC

0.82

ClinPred

0.56

GERP RS

4.5

Varity_R

0.58

gMVP

0.90

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.070

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