9-130494963-G-T

Variant names:

• chr9-130494963-G-T
• rs1261110148
• NM_054012.4:c.1067G>T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_054012.4(ASS1):​c.1067G>T​(p.Gly356Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ASS1 NM_054012.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.29

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.993

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ASS1	NM_054012.4	c.1067G>T	p.Gly356Val	missense_variant	Exon 13 of 15	ENST00000352480.10	NP_446464.1
ASS1	NM_000050.4	c.1067G>T	p.Gly356Val	missense_variant	Exon 14 of 16		NP_000041.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ASS1	ENST00000352480.10	c.1067G>T	p.Gly356Val	missense_variant	Exon 13 of 15	1	NM_054012.4	ENSP00000253004.6
ASS1	ENST00000372393.7	c.1067G>T	p.Gly356Val	missense_variant	Exon 14 of 16	5		ENSP00000361469.2
ASS1	ENST00000372394.5	c.1067G>T	p.Gly356Val	missense_variant	Exon 14 of 16	2		ENSP00000361471.1
ASS1	ENST00000372386.6	n.338G>T		non_coding_transcript_exon_variant	Exon 4 of 6	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Citrullinemia type I Uncertain:1

Jan 11, 2018

Counsyl

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.56
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	1.0	D;D;D
Eigen	Pathogenic	0.83
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.78	.;.;T
M_CAP	Pathogenic	0.69	D
MetaRNN	Pathogenic	0.99	D;D;D
MetaSVM	Pathogenic	0.96	D
MutationAssessor	Pathogenic	4.4	H;H;H
PrimateAI	Uncertain	0.78	T
PROVEAN	Pathogenic	-8.6	D;D;D
REVEL	Pathogenic	0.98
Sift	Uncertain	0.020	D;D;D
Sift4G	Uncertain	0.022	D;D;D
Polyphen		0.78	P;P;P
Vest4		0.97
MutPred		0.94		Gain of ubiquitination at K355 (P = 0.064);Gain of ubiquitination at K355 (P = 0.064);Gain of ubiquitination at K355 (P = 0.064);
MVP		0.98
MPC		0.78
ClinPred		1.0	D
GERP RS		4.6
Varity_R		0.97
gMVP		0.93

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

Publications

LitVar

Other links and lift over

dbSNP: rs1261110148; hg19: chr9-133370350;