rs121908648

Variant names:

• chr9-130489422-A-C
• rs121908648
• NM_054012.4:c.928A>C

Variant summary

Our verdict is Pathogenic. The variant received 13 ACMG points: 13P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5_Moderate

The NM_054012.4(ASS1):​c.928A>C​(p.Lys310Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000109 in 1,461,872 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K310R) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000011 (0 hom.)
• Consequence: ASS1 NM_054012.4 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2 U:1
• Conservation: PhyloP100: 8.72
• Publications: 6 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: Pathogenic. The variant received 13 ACMG points.

• PM1: In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 2 uncertain in NM_054012.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr9-130489423-A-G is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 365260.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.993
• PP5: Variant 9-130489422-A-C is Pathogenic according to our data. Variant chr9-130489422-A-C is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 6339.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ASS1	NM_054012.4	c.928A>C	p.Lys310Gln	missense_variant	Exon 12 of 15	ENST00000352480.10	NP_446464.1
ASS1	NM_000050.4	c.928A>C	p.Lys310Gln	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.928A>C	p.Lys310Gln	missense_variant	Exon 12 of 15	1	NM_054012.4	ENSP00000253004.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000795 AC: 2 AN: 251470 AF XY: 0.0000147

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000109 AC: 16 AN: 1461872 Hom.: 0 Cov.: 33 AF XY: 0.0000151 AC XY: 11 AN XY: 727240

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: 39700

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53402

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

European-Non Finnish (NFE) AF: 0.0000135 AC: 15 AN: 1112010

Other (OTH) AF: 0.00 AC: 0 AN: 60394

GnomAD4 genome Cov.: 32

Alfa AF: 0.00000989 Hom.: 1

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2 Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Citrullinemia type I Pathogenic:1 Uncertain:1

Aug 15, 2004

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Aug 02, 2017

Counsyl

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

Citrullinemia Pathogenic:1

Feb 20, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Lys310 amino acid residue in ASS1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 12815590, 15863597; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 6339). This missense change has been observed in individual(s) with citrullinemia type I (PMID: 12815590, 15266621). This variant is present in population databases (rs121908648, gnomAD 0.002%). This sequence change replaces lysine, which is basic and polar, with glutamine, which is neutral and polar, at codon 310 of the ASS1 protein (p.Lys310Gln). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.82
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.58
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.99	D;D;D
Eigen	Pathogenic	0.94
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.85	.;.;T
M_CAP	Pathogenic	0.79	D
MetaRNN	Pathogenic	0.99	D;D;D
MetaSVM	Pathogenic	0.98	D
MutationAssessor	Pathogenic	4.2	H;H;H
PhyloP100		8.7
PrimateAI	Pathogenic	0.82	D
PROVEAN	Uncertain	-2.9	D;D;D
REVEL	Pathogenic	0.98
Sift	Uncertain	0.0030	D;D;D
Sift4G	Uncertain	0.0060	D;D;D
Polyphen		1.0	D;D;D
Vest4		0.89
MutPred		0.96		Loss of methylation at K310 (P = 0.0057);Loss of methylation at K310 (P = 0.0057);Loss of methylation at K310 (P = 0.0057);
MVP		0.98
MPC		0.97
ClinPred		1.0	D
GERP RS		4.5
Varity_R		0.97
gMVP		0.94
Mutation Taster		=1/99	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs121908648; hg19: chr9-133364809;