6-131573284-T-C

Position:

• chr6-131573284-T-C

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000045.4(ARG1):​c.2T>C​(p.Met1?) variant causes a start lost change. 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 Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ARG1 NM_000045.4 start_lost
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 4.31

Genes affected

ARG1 (HGNC:663): (arginase 1) Arginase catalyzes the hydrolysis of arginine to ornithine and urea. At least two isoforms of mammalian arginase exist (types I and II) which differ in their tissue distribution, subcellular localization, immunologic crossreactivity and physiologic function. The type I isoform encoded by this gene, is a cytosolic enzyme and expressed predominantly in the liver as a component of the urea cycle. Inherited deficiency of this enzyme results in argininemia, an autosomal recessive disorder characterized by hyperammonemia. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Sep 2011]

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PVS1: Start lost variant, no new inframe start found.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 6-131573284-T-C is Pathogenic according to our data. Variant chr6-131573284-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 555971.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ARG1	NM_000045.4	c.2T>C	p.Met1?	start_lost	1/8	ENST00000368087.8	NP_000036.2
ARG1	NM_001244438.2	c.2T>C	p.Met1?	start_lost	1/8		NP_001231367.1
ARG1	NM_001369020.1	c.2T>C	p.Met1?	start_lost	1/6		NP_001355949.1
ARG1	NR_160934.1	n.59T>C		non_coding_transcript_exon_variant	1/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ARG1	ENST00000368087.8	c.2T>C	p.Met1?	start_lost	1/8	1	NM_000045.4	ENSP00000357066	P3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Arginase deficiency Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Feb 24, 2022	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Jan 04, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Apr 23, 2020	For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Ile11 amino acid residue in ARG1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 7649538, 21310339, 22959135, 26310552, 29726057). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. This variant has been observed to be homozygous in an individual affected with arginase deficiency (PMID: 29726057). ClinVar contains an entry for this variant (Variation ID: 555971). This variant is not present in population databases (ExAC no frequency). This sequence change affects the initiator methionine of the ARG1 mRNA. The next in-frame methionine is located at codon 200. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.39
CADD	Benign	22
DANN	Uncertain	0.98
DEOGEN2	Benign	0.41	T;.;.
Eigen	Benign	0.079
Eigen_PC	Benign	0.21
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.90	D;D;D
M_CAP	Pathogenic	0.90	D
MetaRNN	Pathogenic	0.99	D;D;D
MetaSVM	Uncertain	0.23	D
MutationTaster	Benign	1.0	D;D;D
PROVEAN	Benign	-1.1	N;N;.
REVEL	Uncertain	0.61
Sift	Uncertain	0.0020	D;D;.
Sift4G	Uncertain	0.0080	D;D;.
Polyphen		0.11	B;B;.
Vest4		0.91
MutPred		0.97		Gain of catalytic residue at M1 (P = 0.0291);Gain of catalytic residue at M1 (P = 0.0291);Gain of catalytic residue at M1 (P = 0.0291);
MVP		0.98
ClinPred		0.97	D
GERP RS		5.8
Varity_R		0.62
gMVP		0.80

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: rs1554249332; hg19: chr6-131894424;