9-130458525-G-A

Variant names:

• chr9-130458525-G-A
• rs138279074
• NM_054012.4:c.299G>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 3P and 1B. PM1 PP2 BP4

The NM_054012.4(ASS1):​c.299G>A​(p.Arg100His) variant causes a missense change. The variant allele was found at a frequency of 0.000158 in 1,613,208 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R100C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00018 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00016 (0 hom.)
• Consequence: ASS1 NM_054012.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:9
• Conservation: PhyloP100: 3.98
• Publications: 3 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: Uncertain_significance. The variant received 2 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 5 uncertain in NM_054012.4
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 49 curated pathogenic missense variants (we use a threshold of 10). The gene has 4 curated benign missense variants. Gene score misZ: 0.75759 (below the threshold of 3.09). Trascript score misZ: 1.8061 (below the threshold of 3.09). GenCC associations: The gene is linked to citrullinemia type I, adult-onset citrullinemia type I, acute neonatal citrullinemia type I.
• BP4: Computational evidence support a benign effect (MetaRNN=0.34552276).

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.299G>A	p.Arg100His	missense	Exon 4 of 15	NP_446464.1
	ASS1	NM_000050.4		c.299G>A	p.Arg100His	missense	Exon 5 of 16	NP_000041.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ASS1	ENST00000352480.10	TSL:1 MANE Select	c.299G>A	p.Arg100His	missense	Exon 4 of 15	ENSP00000253004.6
	ASS1	ENST00000372393.7	TSL:5	c.299G>A	p.Arg100His	missense	Exon 5 of 16	ENSP00000361469.2
	ASS1	ENST00000372394.5	TSL:2	c.299G>A	p.Arg100His	missense	Exon 5 of 16	ENSP00000361471.1

Frequencies

GnomAD3 genomes AF: 0.000184 AC: 28 AN: 152192 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000785

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.000955

GnomAD2 exomes AF: 0.000180 AC: 45 AN: 250286 AF XY: 0.000185

Gnomad AFR exome AF: 0.000124

Gnomad AMR exome AF: 0.000405

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000142

Gnomad OTH exome AF: 0.000491

GnomAD4 exome AF: 0.000155 AC: 227 AN: 1460900 Hom.: 0 Cov.: 32 AF XY: 0.000162 AC XY: 118 AN XY: 726744

African (AFR) AF: 0.0000598 AC: 2 AN: 33450

American (AMR) AF: 0.000492 AC: 22 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39698

South Asian (SAS) AF: 0.000406 AC: 35 AN: 86208

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53316

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5234

European-Non Finnish (NFE) AF: 0.000139 AC: 154 AN: 1111840

Other (OTH) AF: 0.000216 AC: 13 AN: 60314

GnomAD4 genome AF: 0.000184 AC: 28 AN: 152308 Hom.: 0 Cov.: 33 AF XY: 0.000215 AC XY: 16 AN XY: 74472

African (AFR) AF: 0.0000962 AC: 4 AN: 41580

American (AMR) AF: 0.000784 AC: 12 AN: 15306

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5162

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4824

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

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

European-Non Finnish (NFE) AF: 0.000132 AC: 9 AN: 68026

Other (OTH) AF: 0.000945 AC: 2 AN: 2116

Alfa AF: 0.000177 Hom.: 0

Bravo AF: 0.000291

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000165 AC: 20

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.000178

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	4	-	Citrullinemia type I (4)
-	2	-	not provided (2)
-	1	-	Citrullinemia (1)
-	1	-	Inborn genetic diseases (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Pathogenic	0.23
CADD	Pathogenic	26
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.97	D
Eigen	Benign	0.17
Eigen_PC	Uncertain	0.27
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Uncertain	0.88	D
M_CAP	Uncertain	0.092	D
MetaRNN	Benign	0.35	T
MetaSVM	Pathogenic	0.95	D
MutationAssessor	Uncertain	2.8	M
PhyloP100		4.0
PrimateAI	Uncertain	0.70	T
PROVEAN	Uncertain	-3.0	D
REVEL	Pathogenic	0.71
Sift	Uncertain	0.0080	D
Sift4G	Uncertain	0.037	D
Polyphen		0.11	B
Vest4		0.47
MVP		0.98
MPC		0.33
ClinPred		0.074	T
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.30
gMVP		0.70
Mutation Taster		=3/97	disease causing

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: rs138279074; hg19: chr9-133333912; COSMIC: COSV108884731;