chr9-130489370-T-C

Position:

• chr9-130489370-T-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_054012.4(ASS1):​c.876T>C​(p.His292=) 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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.181

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]

ACMG classification

Verdict is Benign. Variant got -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 id is 92376.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-130489370-T-C is described in Lovd as [Benign].
• 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/exons	MANE	UniProt
ASS1	NM_054012.4	c.876T>C	p.His292=	synonymous_variant	12/15	ENST00000352480.10
ASS1	NM_000050.4	c.876T>C	p.His292=	synonymous_variant	13/16

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ASS1	ENST00000352480.10	c.876T>C	p.His292=	synonymous_variant	12/15	1	NM_054012.4	P1

Frequencies

GnomAD3 genomes AF: 0.103 AC: 15711 AN: 151886 Hom.: 913 Cov.: 31

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

GnomAD3 exomes AF: 0.0914 AC: 22983 AN: 251440 Hom.: 1302 AF XY: 0.0927 AC XY: 12599 AN XY: 135892

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 SAS exome AF: 0.0679

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.: 34 AF XY: 0.0974 AC XY: 70805 AN XY: 727204

Gnomad4 AFR exome AF: 0.117

Gnomad4 AMR exome AF: 0.0495

Gnomad4 ASJ exome AF: 0.0693

Gnomad4 EAS exome AF: 0.00106

Gnomad4 SAS exome AF: 0.0685

Gnomad4 FIN exome AF: 0.174

Gnomad4 NFE exome AF: 0.102

Gnomad4 OTH exome AF: 0.0927

GnomAD4 genome AF: 0.103 AC: 15723 AN: 152004 Hom.: 911 Cov.: 31 AF XY: 0.105 AC XY: 7817 AN XY: 74294

Gnomad4 AFR AF: 0.111

Gnomad4 AMR AF: 0.0621

Gnomad4 ASJ AF: 0.0704

Gnomad4 EAS AF: 0.00193

Gnomad4 SAS AF: 0.0636

Gnomad4 FIN AF: 0.185

Gnomad4 NFE AF: 0.109

Gnomad4 OTH AF: 0.0816

Alfa AF: 0.105 Hom.: 385

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:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Citrullinemia type I Benign:4

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	May 05, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 01, 2021	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jan 02, 2020	- -

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 25, 2013	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. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 19, 2018	- -

Citrullinemia Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.63
CADD	Benign	6.5
DANN	Benign	0.53

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

Other links and lift over

dbSNP: rs1057484; hg19: chr9-133364757; COSMIC: COSV61689835;