NM_054012.4:c.961G>T

Variant names:

• chr9-130489455-G-T
• rs727503813
• NM_054012.4:c.961G>T

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM1 PM2 PP2

The NM_054012.4(ASS1):​c.961G>T​(p.Val321Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,844 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V321M) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: ASS1 NM_054012.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.31
• 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: Uncertain_significance. The variant received 5 ACMG points.

• PM1: In a helix (size 19) in uniprot entity ASSY_HUMAN there are 8 pathogenic changes around while only 0 benign (100%) in NM_054012.4
• PM2: Very rare variant in population databases, with high coverage
• 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ASS1	NM_054012.4	c.961G>T	p.Val321Leu	missense_variant	Exon 12 of 15	ENST00000352480.10	NP_446464.1
ASS1	NM_000050.4	c.961G>T	p.Val321Leu	missense_variant	Exon 13 of 16		NP_000041.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ASS1	ENST00000352480.10	c.961G>T	p.Val321Leu	missense_variant	Exon 12 of 15	1	NM_054012.4	ENSP00000253004.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251324 AF XY: 0.00000736

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461844 Hom.: 0 Cov.: 33 AF XY: 0.00000275 AC XY: 2 AN XY: 727230

African (AFR) AF: 0.0000299 AC: 1 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53392

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111994

Other (OTH) AF: 0.0000166 AC: 1 AN: 60394

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.43
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.17
CADD	Benign	23
DANN	Benign	0.80
DEOGEN2	Pathogenic	0.86	D;D;D
Eigen	Benign	0.12
Eigen_PC	Benign	0.18
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.87	.;.;D
M_CAP	Uncertain	0.090	D
MetaRNN	Uncertain	0.59	D;D;D
MetaSVM	Pathogenic	0.89	D
MutationAssessor	Benign	1.8	L;L;L
PhyloP100		4.3
PrimateAI	Pathogenic	0.82	D
PROVEAN	Benign	-2.0	N;N;N
REVEL	Pathogenic	0.72
Sift	Benign	0.70	T;T;T
Sift4G	Benign	0.45	T;T;T
Polyphen		0.30	B;B;B
Vest4		0.49
MutPred		0.71		Loss of phosphorylation at Y322 (P = 0.1826);Loss of phosphorylation at Y322 (P = 0.1826);Loss of phosphorylation at Y322 (P = 0.1826);
MVP		0.94
MPC		0.37
ClinPred		0.72	D
GERP RS		4.5
Varity_R		0.47
gMVP		0.76
Mutation Taster		=34/66	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: rs727503813; hg19: chr9-133364842;