rs540140

Variant names:

• chr9-130479984-G-T
• rs540140
• NM_054012.4:c.773+184G>T

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.773+184G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.264 in 773,552 control chromosomes in the GnomAD database, including 29,033 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.23 (4726 hom., cov: 34)
  • Exomes 𝑓: 0.27 (24307 hom.)
• Consequence: ASS1 NM_054012.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.689
• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 9-130479984-G-T is Benign according to our data. Variant chr9-130479984-G-T is described in ClinVar as Benign. ClinVar VariationId is 1261532.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.305 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_054012.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ASS1	NM_054012.4	MANE Select	c.773+184G>T		intron	N/A	NP_446464.1
	ASS1	NM_000050.4		c.773+184G>T		intron	N/A	NP_000041.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ASS1	ENST00000352480.10	TSL:1 MANE Select	c.773+184G>T		intron	N/A	ENSP00000253004.6
	ASS1	ENST00000372393.7	TSL:5	c.773+184G>T		intron	N/A	ENSP00000361469.2
	ASS1	ENST00000372394.5	TSL:2	c.773+184G>T		intron	N/A	ENSP00000361471.1

Frequencies

GnomAD3 genomes AF: 0.227 AC: 34513 AN: 152106 Hom.: 4726 Cov.: 34

Gnomad AFR AF: 0.0763

Gnomad AMI AF: 0.436

Gnomad AMR AF: 0.313

Gnomad ASJ AF: 0.282

Gnomad EAS AF: 0.148

Gnomad SAS AF: 0.301

Gnomad FIN AF: 0.226

Gnomad MID AF: 0.155

Gnomad NFE AF: 0.294

Gnomad OTH AF: 0.246

GnomAD4 exome AF: 0.273 AC: 169619 AN: 621328 Hom.: 24307 AF XY: 0.275 AC XY: 91723 AN XY: 333742

African (AFR) AF: 0.0743 AC: 1285 AN: 17294

American (AMR) AF: 0.325 AC: 11737 AN: 36076

Ashkenazi Jewish (ASJ) AF: 0.271 AC: 5509 AN: 20362

East Asian (EAS) AF: 0.142 AC: 4716 AN: 33276

South Asian (SAS) AF: 0.291 AC: 18789 AN: 64618

European-Finnish (FIN) AF: 0.241 AC: 11933 AN: 49580

Middle Eastern (MID) AF: 0.172 AC: 707 AN: 4120

European-Non Finnish (NFE) AF: 0.292 AC: 106293 AN: 363548

Other (OTH) AF: 0.267 AC: 8650 AN: 32454

GnomAD4 genome AF: 0.227 AC: 34521 AN: 152224 Hom.: 4726 Cov.: 34 AF XY: 0.225 AC XY: 16767 AN XY: 74422

African (AFR) AF: 0.0762 AC: 3168 AN: 41564

American (AMR) AF: 0.313 AC: 4782 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.282 AC: 978 AN: 3468

East Asian (EAS) AF: 0.148 AC: 769 AN: 5182

South Asian (SAS) AF: 0.301 AC: 1455 AN: 4830

European-Finnish (FIN) AF: 0.226 AC: 2399 AN: 10602

Middle Eastern (MID) AF: 0.163 AC: 48 AN: 294

European-Non Finnish (NFE) AF: 0.294 AC: 20007 AN: 67970

Other (OTH) AF: 0.246 AC: 519 AN: 2114

Alfa AF: 0.266 Hom.: 10440

Bravo AF: 0.225

Asia WGS AF: 0.225 AC: 782 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

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

Jul 26, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	7.4
DANN	Benign	0.78
PhyloP100		0.69
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs540140; hg19: chr9-133355371; COSMIC: COSV61689103; COSMIC: COSV61689103;