rs1261110148

chr9-130494963-G-Achr9-130494963-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1 PM2 PP3_Strong

The NM_054012.4(ASS1):c.1067G>A(p.Gly356Asp) 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. 12/21 in silico tools predict a damaging outcome for this variant. 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. G356V) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ASS1 NM_054012.4 missense
• Clinical Significance: Not reported in ClinVar
• 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 8 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 2 uncertain in NM_054012.4
• 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/exons	MANE	UniProt
ASS1	NM_054012.4	c.1067G>A	p.Gly356Asp	missense_variant	13/15	ENST00000352480.10
ASS1	NM_000050.4	c.1067G>A	p.Gly356Asp	missense_variant	14/16

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ASS1	ENST00000352480.10	c.1067G>A	p.Gly356Asp	missense_variant	13/15	1	NM_054012.4	P1
ASS1	ENST00000372393.7	c.1067G>A	p.Gly356Asp	missense_variant	14/16	5		P1
ASS1	ENST00000372394.5	c.1067G>A	p.Gly356Asp	missense_variant	14/16	2		P1
ASS1	ENST00000372386.6	n.338G>A		non_coding_transcript_exon_variant	4/6	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Pathogenic	0.57	D
BayesDel_noAF	Pathogenic	0.58
Cadd	Pathogenic	27
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	1.0	D;D;D
Eigen	Pathogenic	0.81
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Uncertain	0.96	D
M_CAP	Pathogenic	0.71	D
MetaRNN	Pathogenic	0.99	D;D;D
MetaSVM	Pathogenic	0.94	D
MutationAssessor	Pathogenic	4.4	H;H;H
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.84	D
PROVEAN	Pathogenic	-6.6	D;D;D
REVEL	Pathogenic	0.98
Sift	Pathogenic	0.0	D;D;D
Sift4G	Pathogenic	0.0010	D;D;D
Polyphen		0.57	P;P;P
Vest4		0.96
MutPred		0.98		Loss of MoRF binding (P = 0.0578);Loss of MoRF binding (P = 0.0578);Loss of MoRF binding (P = 0.0578);
MVP		0.98
MPC		0.65
ClinPred		1.0	D
GERP RS		4.6
Varity_R		0.97
gMVP		0.94

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;