9-130452131-C-T

Variant names:

• chr9-130452131-C-T
• rs75950322
• NM_054012.4:c.-5-93C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_054012.4(ASS1):​c.-5-93C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00108 in 1,123,830 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0050 (8 hom., cov: 32)
  • Exomes 𝑓: 0.00047 (5 hom.)
• Consequence: ASS1 NM_054012.4 intron
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.0590
• 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=-0.62).
• BP6: Variant 9-130452131-C-T is Benign according to our data. Variant chr9-130452131-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 1214955.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00495 (754/152262) while in subpopulation AFR AF = 0.0175 (728/41554). AF 95% confidence interval is 0.0165. There are 8 homozygotes in GnomAd4. There are 374 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 8 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ASS1	NM_054012.4	c.-5-93C>T		intron_variant	Intron 1 of 14	ENST00000352480.10	NP_446464.1
ASS1	NM_000050.4	c.-5-93C>T		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.-5-93C>T		intron_variant	Intron 1 of 14	1	NM_054012.4	ENSP00000253004.6

Frequencies

GnomAD3 genomes AF: 0.00496 AC: 754 AN: 152142 Hom.: 8 Cov.: 32

Gnomad AFR AF: 0.0176

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00144

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: 0.00144

GnomAD4 exome AF: 0.000474 AC: 461 AN: 971568 Hom.: 5 Cov.: 13 AF XY: 0.000426 AC XY: 212 AN XY: 497968

African (AFR) AF: 0.0159 AC: 375 AN: 23512

American (AMR) AF: 0.000702 AC: 25 AN: 35626

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22522

East Asian (EAS) AF: 0.00 AC: 0 AN: 34326

South Asian (SAS) AF: 0.00 AC: 0 AN: 71396

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48438

Middle Eastern (MID) AF: 0.000496 AC: 2 AN: 4034

European-Non Finnish (NFE) AF: 0.00000582 AC: 4 AN: 687782

Other (OTH) AF: 0.00125 AC: 55 AN: 43932

GnomAD4 genome AF: 0.00495 AC: 754 AN: 152262 Hom.: 8 Cov.: 32 AF XY: 0.00502 AC XY: 374 AN XY: 74462

African (AFR) AF: 0.0175 AC: 728 AN: 41554

American (AMR) AF: 0.00144 AC: 22 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68006

Other (OTH) AF: 0.00142 AC: 3 AN: 2110

Alfa AF: 0.00416 Hom.: 0

Bravo AF: 0.00559

Asia WGS AF: 0.00173 AC: 7 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 09, 2020

GeneDx

Significance: Likely 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	-0.62
CADD	Benign	5.4
DANN	Benign	0.58
PhyloP100		0.059
PromoterAI		0.031	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism

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: rs75950322; hg19: chr9-133327518;