9-130452052-T-C

Variant names:

• chr9-130452052-T-C
• rs1760275
• NM_054012.4:c.-5-172T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_054012.4(ASS1):​c.-5-172T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.971 in 700,902 control chromosomes in the GnomAD database, including 330,618 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.95 (68584 hom., cov: 32)
  • Exomes 𝑓: 0.98 (262034 hom.)
• Consequence: ASS1 NM_054012.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.15
• Publications: 5 publications found

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

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.71).
• BP6: Variant 9-130452052-T-C is Benign according to our data. Variant chr9-130452052-T-C is described in ClinVar as [Benign]. Clinvar id is 683297.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.979 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ASS1	NM_054012.4	c.-5-172T>C		intron_variant	Intron 1 of 14	ENST00000352480.10	NP_446464.1
ASS1	NM_000050.4	c.-5-172T>C		intron_variant	Intron 2 of 15		NP_000041.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ASS1	ENST00000352480.10	c.-5-172T>C		intron_variant	Intron 1 of 14	1	NM_054012.4	ENSP00000253004.6

Frequencies

GnomAD3 genomes AF: 0.947 AC: 144125 AN: 152122 Hom.: 68533 Cov.: 32

Gnomad AFR AF: 0.859

Gnomad AMI AF: 0.999

Gnomad AMR AF: 0.975

Gnomad ASJ AF: 0.949

Gnomad EAS AF: 1.00

Gnomad SAS AF: 0.971

Gnomad FIN AF: 0.964

Gnomad MID AF: 0.981

Gnomad NFE AF: 0.985

Gnomad OTH AF: 0.955

GnomAD2 exomes AF: 0.974 AC: 136120 AN: 139790 AF XY: 0.974

Gnomad AFR exome AF: 0.855

Gnomad AMR exome AF: 0.986

Gnomad ASJ exome AF: 0.959

Gnomad EAS exome AF: 1.00

Gnomad FIN exome AF: 0.968

Gnomad NFE exome AF: 0.985

Gnomad OTH exome AF: 0.974

GnomAD4 exome AF: 0.977 AC: 536039 AN: 548662 Hom.: 262034 Cov.: 5 AF XY: 0.977 AC XY: 290060 AN XY: 296822

African (AFR) AF: 0.857 AC: 13402 AN: 15640

American (AMR) AF: 0.985 AC: 33871 AN: 34382

Ashkenazi Jewish (ASJ) AF: 0.958 AC: 18877 AN: 19698

East Asian (EAS) AF: 1.00 AC: 31529 AN: 31532

South Asian (SAS) AF: 0.965 AC: 59746 AN: 61934

European-Finnish (FIN) AF: 0.969 AC: 34280 AN: 35368

Middle Eastern (MID) AF: 0.977 AC: 3913 AN: 4004

European-Non Finnish (NFE) AF: 0.985 AC: 311121 AN: 315960

Other (OTH) AF: 0.972 AC: 29300 AN: 30144

GnomAD4 genome AF: 0.947 AC: 144233 AN: 152240 Hom.: 68584 Cov.: 32 AF XY: 0.947 AC XY: 70512 AN XY: 74438

African (AFR) AF: 0.860 AC: 35677 AN: 41508

American (AMR) AF: 0.975 AC: 14919 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.949 AC: 3296 AN: 3472

East Asian (EAS) AF: 1.00 AC: 5164 AN: 5166

South Asian (SAS) AF: 0.971 AC: 4682 AN: 4822

European-Finnish (FIN) AF: 0.964 AC: 10232 AN: 10618

Middle Eastern (MID) AF: 0.980 AC: 288 AN: 294

European-Non Finnish (NFE) AF: 0.985 AC: 67045 AN: 68032

Other (OTH) AF: 0.956 AC: 2021 AN: 2114

Alfa AF: 0.955 Hom.: 8580

Bravo AF: 0.944

Asia WGS AF: 0.979 AC: 3405 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 14, 2018

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. -

Citrullinemia type I Benign:1

Jul 14, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.71
CADD	Benign	2.1
DANN	Benign	0.80
PhyloP100		-1.1
PromoterAI		-0.058	Neutral
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs1760275; hg19: chr9-133327439;