rs1057484

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_054012.4(ASS1):c.876T>C(p.His292His) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0984 in 1,613,790 control chromosomes in the GnomAD database, including 8,636 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.10 ( 911 hom., cov: 31)

Exomes 𝑓: 0.098 ( 7725 hom. )

Consequence

ASS1
NM_054012.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: -0.181

Publications

15 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: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.63).

BP6

Variant 9-130489370-T-C is Benign according to our data. Variant chr9-130489370-T-C is described in ClinVar as Benign. ClinVar VariationId is 92376.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.181 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.108 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ASS1	NM_054012.4 link	c.876T>C	p.His292His	synonymous_variant	Exon 12 of 15	ENST00000352480.10	NP_446464.1	P00966Q5T6L4
ASS1	NM_000050.4 link	c.876T>C	p.His292His	synonymous_variant	Exon 13 of 16		NP_000041.2	P00966Q5T6L4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ASS1	ENST00000352480.10 link	c.876T>C	p.His292His	synonymous_variant	Exon 12 of 15	1	NM_054012.4	ENSP00000253004.6		P00966

Frequencies

GnomAD3 genomes

AF:

0.103

AC:

15711

AN:

151886

Hom.:

913

Cov.:

show subpopulations

Gnomad AFR

AF:

0.111

Gnomad AMI

AF:

0.0921

Gnomad AMR

AF:

0.0622

Gnomad ASJ

AF:

0.0704

Gnomad EAS

AF:

0.00193

Gnomad SAS

AF:

0.0642

Gnomad FIN

AF:

0.185

Gnomad MID

AF:

0.0696

Gnomad NFE

AF:

0.109

Gnomad OTH

AF:

0.0825

GnomAD2 exomes

AF:

0.0914

AC:

22983

AN:

251440

AF XY:

0.0927

show subpopulations

Gnomad AFR exome

AF:

0.115

Gnomad AMR exome

AF:

0.0472

Gnomad ASJ exome

AF:

0.0691

Gnomad EAS exome

AF:

0.00158

Gnomad FIN exome

AF:

0.175

Gnomad NFE exome

AF:

0.108

Gnomad OTH exome

AF:

0.0985

GnomAD4 exome

AF:

0.0979

AC:

143143

AN:

1461786

Hom.:

7725

Cov.:

AF XY:

0.0974

AC XY:

70805

AN XY:

727204

show subpopulations

African (AFR)

AF:

0.117

AC:

3908

AN:

33474

American (AMR)

AF:

0.0495

AC:

2212

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.0693

AC:

1810

AN:

26136

East Asian (EAS)

AF:

0.00106

AC:

AN:

39700

South Asian (SAS)

AF:

0.0685

AC:

5910

AN:

86258

European-Finnish (FIN)

AF:

0.174

AC:

9291

AN:

53362

Middle Eastern (MID)

AF:

0.0956

AC:

551

AN:

5766

European-Non Finnish (NFE)

AF:

0.102

AC:

113819

AN:

1111974

Other (OTH)

AF:

0.0927

AC:

5600

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

8073

16146

24218

32291

40364

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

4012

8024

12036

16048

20060

<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:

0.103

AC:

15723

AN:

152004

Hom.:

911

Cov.:

AF XY:

0.105

AC XY:

7817

AN XY:

74294

show subpopulations

African (AFR)

AF:

0.111

AC:

4608

AN:

41452

American (AMR)

AF:

0.0621

AC:

948

AN:

15270

Ashkenazi Jewish (ASJ)

AF:

0.0704

AC:

244

AN:

3468

East Asian (EAS)

AF:

0.00193

AC:

AN:

5172

South Asian (SAS)

AF:

0.0636

AC:

306

AN:

4808

European-Finnish (FIN)

AF:

0.185

AC:

1949

AN:

10552

Middle Eastern (MID)

AF:

0.0680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.109

AC:

7382

AN:

67968

Other (OTH)

AF:

0.0816

AC:

172

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

Heterozygous variant carriers

721

1442

2164

2885

3606

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

182

364

546

728

910

<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:

0.105

Hom.:

390

Bravo

AF:

0.0951

Asia WGS

AF:

0.0430

AC:

152

AN:

3478

EpiCase

AF:

0.103

EpiControl

AF:

0.102

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Citrullinemia type I

Benign:4

Jan 02, 2020

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 05, 2017

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jul 01, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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:3

Jul 25, 2013

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Jun 19, 2018

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Citrullinemia

Benign:1

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.63

CADD

Benign

6.5

(source)

DANN

Benign

0.53

PhyloP100

-0.18

Mutation Taster

=99/1

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over