rs763389916

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2PP3_ModeratePP5_Very_Strong

The NM_054012.4(ASS1):c.773+49C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000705 in 1,561,222 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000064 ( 0 hom. )

Consequence

ASS1
NM_054012.4 intron

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3O:1

Conservation

PhyloP100: 1.23

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 Pathogenic. Variant got 12 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

PP5

Variant 9-130479849-C-T is Pathogenic according to our data. Variant chr9-130479849-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 265958.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-130479849-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ASS1	NM_054012.4 linkuse as main transcript	c.773+49C>T		intron_variant		ENST00000352480.10
ASS1	NM_000050.4 linkuse as main transcript	c.773+49C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ASS1	ENST00000352480.10 linkuse as main transcript	c.773+49C>T		intron_variant		1	NM_054012.4	P1

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152236

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:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000200

AC:

AN:

250374

Hom.:

AF XY:

0.0000148

AC XY:

AN XY:

135474

show subpopulations

Gnomad AFR exome

AF:

0.000185

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000177

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000639

AC:

AN:

1408986

Hom.:

Cov.:

AF XY:

0.00000426

AC XY:

AN XY:

703980

show subpopulations

Gnomad4 AFR exome

AF:

0.0000621

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000254

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000564

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152236

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74364

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:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000756

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Citrullinemia type I

Pathogenic:2Other:1

not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Aug 20, 2022	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	May 02, 2017	- -

Citrullinemia

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Dec 12, 2023

This sequence change falls in intron 11 of the ASS1 gene. It does not directly change the encoded amino acid sequence of the ASS1 protein. This variant is present in population databases (rs763389916, gnomAD 0.02%). This variant has been observed in individuals with citrullinemia (PMID: 14680976, 28132756). ClinVar contains an entry for this variant (Variation ID: 265958). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.80

Cadd

Uncertain

Dann

Benign

0.82

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.98

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.98

Position offset: -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