rs371265106

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 17 ACMG points: 17P and 0B. PM1PM2PP2PP3_StrongPP5_Very_Strong

The NM_054012.4(ASS1):c.836G>A(p.Arg279Gln) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000744 in 1,613,898 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 14/24 in silico tools predict a damaging outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000062 ( 0 hom. )

Consequence

ASS1
NM_054012.4 missense, splice_region

Scores

Splicing: ADA: 0.7328

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8

Conservation

PhyloP100: 9.26

Publications

8 publications found

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 Gene-Disease associations (from GenCC):

citrullinemia type I
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, Myriad Women’s Health, G2P
acute neonatal citrullinemia type I
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
adult-onset citrullinemia type I
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ASS1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 17 ACMG points.

PM1

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

PM2

Very rare variant in population databases, with high coverage;

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 49 curated pathogenic missense variants (we use a threshold of 10). The gene has 4 curated benign missense variants. Gene score misZ: 0.75759 (below the threshold of 3.09). Trascript score misZ: 1.8061 (below the threshold of 3.09). GenCC associations: The gene is linked to citrullinemia type I, adult-onset citrullinemia type I, acute neonatal citrullinemia type I.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.961

PP5

Variant 9-130480447-G-A is Pathogenic according to our data. Variant chr9-130480447-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 92375.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ASS1	NM_054012.4 link	c.836G>A	p.Arg279Gln	missense_variant, splice_region_variant	Exon 11 of 15	ENST00000352480.10	NP_446464.1
ASS1	NM_000050.4 link	c.836G>A	p.Arg279Gln	missense_variant, splice_region_variant	Exon 12 of 16		NP_000041.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ASS1	ENST00000352480.10 link	c.836G>A	p.Arg279Gln	missense_variant, splice_region_variant	Exon 11 of 15	1	NM_054012.4	ENSP00000253004.6

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152234

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000482

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000199

AC:

AN:

250872

AF XY:

0.00000737

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000145

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000616

AC:

AN:

1461664

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

727114

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33480

American (AMR)

AF:

0.000134

AC:

AN:

44712

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26132

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39698

South Asian (SAS)

AF:

0.00

AC:

AN:

86232

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53284

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5758

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1111974

Other (OTH)

AF:

0.00

AC:

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152234

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74372

show subpopulations

African (AFR)

AF:

0.0000482

AC:

AN:

41460

American (AMR)

AF:

0.0000654

AC:

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5194

South Asian (SAS)

AF:

0.00

AC:

AN:

4836

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68038

Other (OTH)

AF:

0.00

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000239

Hom.:

Bravo

AF:

0.0000151

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Citrullinemia type I

Pathogenic:5

Jun 01, 2016

Counsyl

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

Jul 20, 2021

Fulgent Genetics, Fulgent Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 29, 2024

Baylor Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 06, 2023

Revvity Omics, Revvity

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 04, 2023

3billion

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.002%). Predicted Consequence/Location: Missense variant In silico tool predictions suggest damaging effect of the variant on gene or gene product [REVEL: 0.97 (>=0.6, sensitivity 0.68 and specificity 0.92); 3Cnet: 0.93 (>=0.6, sensitivity 0.72 and precision 0.9)]. Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000092375 /PMID: 9090528).The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least 2 similarly affected unrelated individuals (PMID: 16475226, 23099195, 9090528). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -

not provided

Pathogenic:2

Oct 08, 2012

Eurofins Ntd Llc (ga)

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 03, 2017

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Citrullinemia

Pathogenic:1

Dec 12, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 279 of the ASS1 protein (p.Arg279Gln). This variant is present in population databases (rs371265106, gnomAD 0.01%). This missense change has been observed in individual(s) with citrulllinemia type I (PMID: 9090528, 16475226, 23099195; internal data). 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: 92375). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.98

BayesDel_addAF

Pathogenic

0.38

BayesDel_noAF

Pathogenic

0.57

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

1.0

D;D;D

Eigen

Pathogenic

0.85

Eigen_PC

Pathogenic

0.77

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.94

.;.;D

M_CAP

Pathogenic

0.66

MetaRNN

Pathogenic

0.96

D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

4.3

H;H;H

PhyloP100

9.3

PrimateAI

Pathogenic

0.81

PROVEAN

Uncertain

-3.9

D;D;D

REVEL

Pathogenic

0.97

Sift

Uncertain

0.0010

D;D;D

Sift4G

Uncertain

0.023

D;D;D

Polyphen

0.99

D;D;D

Vest4

0.99

MVP

0.98

MPC

0.74

ClinPred

0.99

GERP RS

4.7

Varity_R

0.98

gMVP

0.95

Mutation Taster

=25/75

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.73

dbscSNV1_RF

Pathogenic

0.72

Splicevardb

2.0

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over