6-131573286-A-G

Position:

• chr6-131573286-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1 PM2

The NM_000045.4(ARG1):​c.4A>G​(p.Ser2Gly) variant causes a missense change. The variant allele was found at a frequency of 0.0000171 in 1,461,838 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S2I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000017 (0 hom.)
• Consequence: ARG1 NM_000045.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.49

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 Uncertain_significance. Variant got 4 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in NM_000045.4
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ARG1	NM_000045.4	c.4A>G	p.Ser2Gly	missense_variant	1/8	ENST00000368087.8
ARG1	NM_001244438.2	c.4A>G	p.Ser2Gly	missense_variant	1/8
ARG1	NM_001369020.1	c.4A>G	p.Ser2Gly	missense_variant	1/6
ARG1	NR_160934.1	n.61A>G		non_coding_transcript_exon_variant	1/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ARG1	ENST00000368087.8	c.4A>G	p.Ser2Gly	missense_variant	1/8	1	NM_000045.4	P3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.0000171 AC: 25 AN: 1461838 Hom.: 0 Cov.: 30 AF XY: 0.0000124 AC XY: 9 AN XY: 727226

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000225

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Arginase deficiency Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 31, 2021

This variant is not present in population databases (gnomAD no frequency). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. This variant has not been reported in the literature in individuals affected with ARG1-related conditions. This sequence change replaces serine, which is neutral and polar, with glycine, which is neutral and non-polar, at codon 2 of the ARG1 protein (p.Ser2Gly). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.099
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.030
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.44	T;.;.
Eigen	Benign	-0.16
Eigen_PC	Benign	0.057
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.38	T;T;T
M_CAP	Benign	0.077	D
MetaRNN	Uncertain	0.66	D;D;D
MetaSVM	Benign	-0.35	T
MutationAssessor	Uncertain	2.4	M;M;M
MutationTaster	Benign	0.70	D;D;D
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-1.6	N;N;.
REVEL	Uncertain	0.33
Sift	Uncertain	0.019	D;D;.
Sift4G	Benign	0.11	T;T;.
Polyphen		0.0090	B;B;.
Vest4		0.40
MutPred		0.29		Loss of stability (P = 0.0402);Loss of stability (P = 0.0402);Loss of stability (P = 0.0402);
MVP		0.98
MPC		0.31
ClinPred		0.96	D
GERP RS		5.8
Varity_R		0.26
gMVP		0.42

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr6-131894426;