9-130450320-G-A

Variant names:

• chr9-130450320-G-A
• rs184403245
• NM_054012.4:c.-5-1904G>A

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.-5-1904G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000847 in 987,548 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0037 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00034 (3 hom.)
• Consequence: ASS1 NM_054012.4 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.512
• Publications: 1 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 9-130450320-G-A is Benign according to our data. Variant chr9-130450320-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 382981.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00365 (556/152282) while in subpopulation AFR AF = 0.0131 (545/41552). AF 95% confidence interval is 0.0122. There are 0 homozygotes in GnomAd4. There are 268 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ASS1	NM_054012.4	c.-5-1904G>A		intron_variant	Intron 1 of 14	ENST00000352480.10	NP_446464.1
ASS1	NM_000050.4	c.-19G>A		5_prime_UTR_variant	Exon 2 of 16		NP_000041.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ASS1	ENST00000352480.10	c.-5-1904G>A		intron_variant	Intron 1 of 14	1	NM_054012.4	ENSP00000253004.6
ASS1	ENST00000372393.7	c.-19G>A		5_prime_UTR_variant	Exon 2 of 16	5		ENSP00000361469.2
ASS1	ENST00000372394.5	c.-447-1282G>A		intron_variant	Intron 1 of 15	2		ENSP00000361471.1
ASS1	ENST00000422569.5	c.-5-1904G>A		intron_variant	Intron 1 of 7	5		ENSP00000394212.1

Frequencies

GnomAD3 genomes AF: 0.00365 AC: 555 AN: 152164 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0131

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000524

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: 0.0000294

Gnomad OTH AF: 0.000478

GnomAD4 exome AF: 0.000335 AC: 280 AN: 835266 Hom.: 3 Cov.: 29 AF XY: 0.000308 AC XY: 119 AN XY: 385874

African (AFR) AF: 0.0165 AC: 262 AN: 15842

American (AMR) AF: 0.00101 AC: 1 AN: 992

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 5158

East Asian (EAS) AF: 0.00 AC: 0 AN: 3634

South Asian (SAS) AF: 0.0000606 AC: 1 AN: 16510

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 820

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2608

European-Non Finnish (NFE) AF: 0.00000394 AC: 3 AN: 762232

Other (OTH) AF: 0.000473 AC: 13 AN: 27470

GnomAD4 genome AF: 0.00365 AC: 556 AN: 152282 Hom.: 0 Cov.: 33 AF XY: 0.00360 AC XY: 268 AN XY: 74480

African (AFR) AF: 0.0131 AC: 545 AN: 41552

American (AMR) AF: 0.000523 AC: 8 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

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

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68014

Other (OTH) AF: 0.000473 AC: 1 AN: 2112

Alfa AF: 0.00243 Hom.: 0

Bravo AF: 0.00380

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Aug 01, 2018

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	0.21
DANN	Benign	0.67
PhyloP100		-0.51

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: rs184403245; hg19: chr9-133325707; COSMIC: COSV100752475; COSMIC: COSV100752475;