rs1554250510

Variant names:

• chr6-131579187-T-G
• rs1554250510
• NM_000045.4:c.207T>G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_000045.4(ARG1):​c.207T>G​(p.Asn69Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ARG1 NM_000045.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.324

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]

MED23 (HGNC:2372): (mediator complex subunit 23) The activation of gene transcription is a multistep process that is triggered by factors that recognize transcriptional enhancer sites in DNA. These factors work with co-activators to direct transcriptional initiation by the RNA polymerase II apparatus. The protein encoded by this gene is a subunit of the CRSP (cofactor required for SP1 activation) complex, which, along with TFIID, is required for efficient activation by SP1. This protein is also a component of other multisubunit complexes e.g. thyroid hormone receptor-(TR-) associated proteins which interact with TR and facilitate TR function on DNA templates in conjunction with initiation factors and cofactors. This protein also acts as a metastasis suppressor. Several alternatively spliced transcript variants encoding different isoforms have been described for this gene. [provided by RefSeq, Jul 2012]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ARG1	NM_000045.4	c.207T>G	p.Asn69Lys	missense_variant	Exon 3 of 8	ENST00000368087.8	NP_000036.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ARG1	ENST00000368087.8	c.207T>G	p.Asn69Lys	missense_variant	Exon 3 of 8	1	NM_000045.4	ENSP00000357066.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Arginase deficiency Uncertain:1

Aug 25, 2017

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces asparagine with lysine at codon 69 of the ARG1 protein (p.Asn69Lys). The asparagine residue is highly conserved and there is a moderate physicochemical difference between asparagine and lysine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with ARG1-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.50
BayesDel_addAF	Benign	-0.059	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	14
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.88	D;.;.
Eigen	Benign	-0.16
Eigen_PC	Benign	-0.23
FATHMM_MKL	Benign	0.45	N
LIST_S2	Uncertain	0.86	D;T;T
M_CAP	Benign	0.070	D
MetaRNN	Uncertain	0.46	T;T;T
MetaSVM	Benign	-0.33	T
MutationAssessor	Uncertain	2.3	M;.;M
PrimateAI	Uncertain	0.55	T
PROVEAN	Uncertain	-3.6	D;D;.
REVEL	Uncertain	0.43
Sift	Benign	0.069	T;T;.
Sift4G	Benign	0.22	T;T;.
Polyphen		0.85	P;P;.
Vest4		0.48
MutPred		0.58		Gain of methylation at N69 (P = 0.0143);.;Gain of methylation at N69 (P = 0.0143);
MVP		0.90
MPC		0.17
ClinPred		0.91	D
GERP RS		-1.8
Varity_R		0.58
gMVP		0.52

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: rs1554250510; hg19: chr6-131900327;