rs555388438

Positions:

chr9-130494900-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2PM5PP3_ModeratePP5

The NM_054012.4(ASS1):c.1004G>A(p.Arg335His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000211 in 1,613,408 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. R335C) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.000053 ( 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:1U:1

Conservation

PhyloP100: 7.46

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 7 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr9-130494899-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 528370.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=2, Likely_pathogenic=1, Pathogenic=1}.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.885

PP5

Variant 9-130494900-G-A is Pathogenic according to our data. Variant chr9-130494900-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 555009.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ASS1	NM_054012.4 linkuse as main transcript	c.1004G>A	p.Arg335His	missense_variant	13/15	ENST00000352480.10
ASS1	NM_000050.4 linkuse as main transcript	c.1004G>A	p.Arg335His	missense_variant	14/16

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
ASS1	ENST00000352480.10 linkuse as main transcript	c.1004G>A	p.Arg335His	missense_variant	13/15	1	NM_054012.4	P1
ASS1	ENST00000372393.7 linkuse as main transcript	c.1004G>A	p.Arg335His	missense_variant	14/16	5		P1
ASS1	ENST00000372394.5 linkuse as main transcript	c.1004G>A	p.Arg335His	missense_variant	14/16	2		P1
ASS1	ENST00000372386.6 linkuse as main transcript	n.275G>A		non_coding_transcript_exon_variant	4/6	3

Frequencies

GnomAD3 genomes

AF:

0.0000526

AC:

AN:

152174

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000882

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000518

AC:

AN:

251166

Hom.:

AF XY:

0.0000516

AC XY:

AN XY:

135774

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000145

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000109

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000440

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000178

AC:

AN:

1461116

Hom.:

Cov.:

AF XY:

0.0000220

AC XY:

AN XY:

726872

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.000112

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000171

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000525

AC:

AN:

152292

Hom.:

Cov.:

AF XY:

0.0000403

AC XY:

AN XY:

74464

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000882

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000148

Hom.:

Bravo

AF:

0.0000567

ExAC

AF:

0.0000165

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Citrullinemia

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jan 30, 2024

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 335 of the ASS1 protein (p.Arg335His). This variant is present in population databases (rs555388438, gnomAD 0.01%). This missense change has been observed in individual(s) with citrullinemia and/or elevated citrulline (PMID: 28111830, 31737040; Invitae). 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: 555009). 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%. This variant disrupts the p.Arg335 amino acid residue in ASS1. Other variant(s) that disrupt this residue have been determined to be pathogenic (Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Citrullinemia type I

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Counsyl

Nov 10, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.23

BayesDel_addAF

Pathogenic

0.29

BayesDel_noAF

Pathogenic

0.44

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.96

D;D;D

Eigen

Pathogenic

0.72

Eigen_PC

Pathogenic

0.69

FATHMM_MKL

Uncertain

0.94

LIST_S2

Benign

0.84

.;.;T

M_CAP

Uncertain

0.20

MetaRNN

Pathogenic

0.88

D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Uncertain

2.7

M;M;M

MutationTaster

Benign

1.0

D;D;D;D

PrimateAI

Uncertain

0.75

PROVEAN

Uncertain

-3.6

D;D;D

REVEL

Pathogenic

0.92

Sift

Uncertain

0.025

D;D;D

Sift4G

Uncertain

0.030

D;D;D

Polyphen

1.0

D;D;D

Vest4

0.81

MVP

0.98

MPC

0.48

ClinPred

0.74

GERP RS

4.8

Varity_R

0.73

gMVP

0.78

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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