rs74923032

Positions:

chr9-130479793-G-A

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1BP4_StrongBP6_Very_StrongBS1BS2

The NM_054012.4(ASS1):c.766G>A(p.Glu256Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00171 in 1,613,998 control chromosomes in the GnomAD database, including 41 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0086 ( 16 hom., cov: 33)

Exomes 𝑓: 0.00099 ( 25 hom. )

Consequence

ASS1
NM_054012.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 7.00

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 Benign. Variant got -18 ACMG points.

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_054012.4

BP4

Computational evidence support a benign effect (MetaRNN=0.009927303).

BP6

Variant 9-130479793-G-A is Benign according to our data. Variant chr9-130479793-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 235312.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00859 (1309/152334) while in subpopulation AFR AF= 0.0294 (1223/41578). AF 95% confidence interval is 0.028. There are 16 homozygotes in gnomad4. There are 624 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 16 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ASS1	NM_054012.4 linkuse as main transcript	c.766G>A	p.Glu256Lys	missense_variant	10/15	ENST00000352480.10
ASS1	NM_000050.4 linkuse as main transcript	c.766G>A	p.Glu256Lys	missense_variant	11/16

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ASS1	ENST00000352480.10 linkuse as main transcript	c.766G>A	p.Glu256Lys	missense_variant	10/15	1	NM_054012.4	P1

Frequencies

GnomAD3 genomes

AF:

0.00859

AC:

1307

AN:

152216

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0295

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00379

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000620

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000162

Gnomad OTH

AF:

0.00621

GnomAD3 exomes

AF:

0.00220

AC:

554

AN:

251460

Hom.:

AF XY:

0.00167

AC XY:

227

AN XY:

135918

show subpopulations

Gnomad AFR exome

AF:

0.0290

Gnomad AMR exome

AF:

0.00165

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000980

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000106

Gnomad OTH exome

AF:

0.00163

GnomAD4 exome

AF:

0.000993

AC:

1452

AN:

1461664

Hom.:

Cov.:

AF XY:

0.000857

AC XY:

623

AN XY:

727166

show subpopulations

Gnomad4 AFR exome

AF:

0.0311

Gnomad4 AMR exome

AF:

0.00217

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0000928

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.000137

Gnomad4 OTH exome

AF:

0.00224

GnomAD4 genome

AF:

0.00859

AC:

1309

AN:

152334

Hom.:

Cov.:

AF XY:

0.00838

AC XY:

624

AN XY:

74490

show subpopulations

Gnomad4 AFR

AF:

0.0294

Gnomad4 AMR

AF:

0.00379

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000621

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000162

Gnomad4 OTH

AF:

0.00614

Alfa

AF:

0.00161

Hom.:

Bravo

AF:

0.00999

ESP6500AA

AF:

0.0306

AC:

135

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.00278

AC:

337

Asia WGS

AF:

0.00289

AC:

AN:

3478

EpiCase

AF:

0.000109

EpiControl

AF:

0.000178

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Citrullinemia type I

Benign:2

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Apr 13, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Feb 11, 2016

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Citrullinemia

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Feb 11, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.094

BayesDel_addAF

Benign

-0.19

BayesDel_noAF

Uncertain

-0.030

CADD

Uncertain

DANN

Benign

0.95

DEOGEN2

Pathogenic

0.83

D;D;D

Eigen

Benign

-0.20

Eigen_PC

Benign

-0.036

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.90

.;.;D

MetaRNN

Benign

0.0099

T;T;T

MetaSVM

Uncertain

0.30

MutationAssessor

Benign

0.67

N;N;N

MutationTaster

Benign

1.0

D;D;D;D

PrimateAI

Uncertain

0.60

PROVEAN

Benign

-1.6

N;N;N

REVEL

Uncertain

0.49

Sift

Benign

0.48

T;T;T

Sift4G

Benign

0.59

T;T;T

Polyphen

0.0040

B;B;B

Vest4

0.46

MVP

0.95

MPC

0.30

ClinPred

0.017

GERP RS

4.9

Varity_R

0.38

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

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