rs373514077

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM5PP2PP3PP5

The NM_000050.4(ASS1):c.1003C>T(p.Arg335Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000948 in 1,613,382 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. R335H) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.000092 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000095 ( 0 hom. )

Consequence

ASS1
NM_000050.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4U:2

Conservation

PhyloP100: 5.61

Publications

4 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: Uncertain_significance. The variant received 5 ACMG points.

PM5

Other missense variant is known to change same aminoacid residue: Variant chr9-130494900-G-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 555009.Status of the report is criteria_provided_single_submitter, 1 stars.

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, 0.824

PP5

Variant 9-130494899-C-T is Pathogenic according to our data. Variant chr9-130494899-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 528370.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000050.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ASS1	NM_054012.4	MANE Select	c.1003C>T	p.Arg335Cys	missense	Exon 13 of 15	NP_446464.1
	ASS1	NM_000050.4		c.1003C>T	p.Arg335Cys	missense	Exon 14 of 16	NP_000041.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
ASS1	ENST00000352480.10	TSL:1 MANE Select	c.1003C>T	p.Arg335Cys	missense	Exon 13 of 15	ENSP00000253004.6
ASS1	ENST00000852201.1		c.1198C>T	p.Arg400Cys	missense	Exon 14 of 16	ENSP00000522260.1
ASS1	ENST00000852207.1		c.1126C>T	p.Arg376Cys	missense	Exon 14 of 16	ENSP00000522266.1

Frequencies

GnomAD3 genomes

AF:

0.0000920

AC:

AN:

152136

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

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:

0.0000735

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000195

AC:

AN:

251188

AF XY:

0.000184

show subpopulations

Gnomad AFR exome

AF:

0.000308

Gnomad AMR exome

AF:

0.000491

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000440

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000951

AC:

139

AN:

1461128

Hom.:

Cov.:

AF XY:

0.000111

AC XY:

AN XY:

726884

show subpopulations

African (AFR)

AF:

0.000149

AC:

AN:

33462

American (AMR)

AF:

0.000492

AC:

AN:

44714

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26132

East Asian (EAS)

AF:

0.000277

AC:

AN:

39700

South Asian (SAS)

AF:

0.000592

AC:

AN:

86218

European-Finnish (FIN)

AF:

0.0000375

AC:

AN:

53382

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5360

European-Non Finnish (NFE)

AF:

0.0000324

AC:

AN:

1111844

Other (OTH)

AF:

0.000199

AC:

AN:

60316

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.472

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:

0.0000920

AC:

AN:

152254

Hom.:

Cov.:

AF XY:

0.000121

AC XY:

AN XY:

74440

show subpopulations

African (AFR)

AF:

0.000120

AC:

AN:

41548

American (AMR)

AF:

0.000196

AC:

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5170

South Asian (SAS)

AF:

0.000208

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000735

AC:

AN:

68008

Other (OTH)

AF:

0.00

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.543

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.0000901

Hom.:

Bravo

AF:

0.0000869

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000165

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.000119

ClinVar

ClinVar submissions as Germline

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Citrullinemia type I (4)

Citrullinemia (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.28

BayesDel_addAF

Pathogenic

0.23

BayesDel_noAF

Pathogenic

0.47

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.97

Eigen

Uncertain

0.64

Eigen_PC

Uncertain

0.61

FATHMM_MKL

Uncertain

0.92

LIST_S2

Uncertain

0.88

M_CAP

Pathogenic

0.61

MetaRNN

Pathogenic

0.82

MetaSVM

Pathogenic

1.1

MutationAssessor

Uncertain

2.9

PhyloP100

5.6

PrimateAI

Pathogenic

0.80

PROVEAN

Pathogenic

-5.5

REVEL

Pathogenic

0.91

Sift

Benign

0.070

Sift4G

Uncertain

0.0060

Polyphen

0.90

Vest4

0.85

MVP

0.98

MPC

0.71

ClinPred

0.33

GERP RS

4.8

Varity_R

0.75

gMVP

0.82

Mutation Taster

=19/81

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over