9-130450341-C-T

Variant names:

• chr9-130450341-C-T
• rs12004384
• NM_054012.4:c.-5-1883C>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_054012.4(ASS1):​c.-5-1883C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00251 in 987,336 control chromosomes in the GnomAD database, including 38 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.010 (26 hom., cov: 33)
  • Exomes 𝑓: 0.0011 (12 hom.)
• Consequence: ASS1 NM_054012.4 intron
• Scores: Splicing: ADA: 0.00001812
• Clinical Significance: Benign criteria provided, single submitter B:2
• Conservation: PhyloP100: 0.296
• Publications: 4 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 9-130450341-C-T is Benign according to our data. Variant chr9-130450341-C-T is described in ClinVar as [Benign]. Clinvar id is 381450.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0101 (1532/152318) while in subpopulation AFR AF = 0.0346 (1437/41562). AF 95% confidence interval is 0.0331. There are 26 homozygotes in GnomAd4. There are 730 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 26 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ASS1	NM_054012.4	c.-5-1883C>T		intron_variant	Intron 1 of 14	ENST00000352480.10	NP_446464.1
ASS1	NM_000050.4	c.-6+8C>T		splice_region_variant, 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.-5-1883C>T		intron_variant	Intron 1 of 14	1	NM_054012.4	ENSP00000253004.6
ASS1	ENST00000372393.7	c.-6+8C>T		splice_region_variant, intron_variant	Intron 2 of 15	5		ENSP00000361469.2
ASS1	ENST00000372394.5	c.-447-1261C>T		intron_variant	Intron 1 of 15	2		ENSP00000361471.1
ASS1	ENST00000422569.5	c.-5-1883C>T		intron_variant	Intron 1 of 7	5		ENSP00000394212.1

Frequencies

GnomAD3 genomes AF: 0.0100 AC: 1529 AN: 152200 Hom.: 26 Cov.: 33

Gnomad AFR AF: 0.0346

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00432

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000265

Gnomad OTH AF: 0.00478

GnomAD4 exome AF: 0.00114 AC: 951 AN: 835018 Hom.: 12 Cov.: 29 AF XY: 0.00107 AC XY: 413 AN XY: 385746

African (AFR) AF: 0.0368 AC: 583 AN: 15832

American (AMR) AF: 0.00301 AC: 3 AN: 998

Ashkenazi Jewish (ASJ) AF: 0.000194 AC: 1 AN: 5160

East Asian (EAS) AF: 0.00 AC: 0 AN: 3642

South Asian (SAS) AF: 0.00 AC: 0 AN: 16498

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 872

Middle Eastern (MID) AF: 0.00703 AC: 16 AN: 2276

European-Non Finnish (NFE) AF: 0.000356 AC: 271 AN: 762256

Other (OTH) AF: 0.00280 AC: 77 AN: 27484

GnomAD4 genome AF: 0.0101 AC: 1532 AN: 152318 Hom.: 26 Cov.: 33 AF XY: 0.00980 AC XY: 730 AN XY: 74480

African (AFR) AF: 0.0346 AC: 1437 AN: 41562

American (AMR) AF: 0.00431 AC: 66 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000265 AC: 18 AN: 68032

Other (OTH) AF: 0.00473 AC: 10 AN: 2112

Alfa AF: 0.0103 Hom.: 2

Bravo AF: 0.0114

Asia WGS AF: 0.00231 AC: 8 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Dec 10, 2015

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

Apr 09, 2018

Natera, Inc.

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	7.7
DANN	Benign	0.44
PhyloP100		0.30
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000018
dbscSNV1_RF	Benign	0.0
SpliceAI score (max)		0.060		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: rs12004384; hg19: chr9-133325728;