6-131583808-C-G

Variant names:

• chr6-131583808-C-G
• rs104893942
• NM_000045.4:c.869C>G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP5

The NM_000045.4(ARG1):​c.869C>G​(p.Thr290Ser) 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 Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ARG1 NM_000045.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 2.65

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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 6-131583808-C-G is Pathogenic according to our data. Variant chr6-131583808-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 2389.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr6-131583808-C-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ARG1	NM_000045.4	c.869C>G	p.Thr290Ser	missense_variant	Exon 8 of 8	ENST00000368087.8	NP_000036.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ARG1	ENST00000368087.8	c.869C>G	p.Thr290Ser	missense_variant	Exon 8 of 8	1	NM_000045.4	ENSP00000357066.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Arginase deficiency Pathogenic:1

Jun 01, 1992

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.099
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.0
CADD	Benign	16
DANN	Uncertain	0.98
DEOGEN2	Benign	0.40	T;.;.
Eigen	Benign	-0.83
Eigen_PC	Benign	-0.63
FATHMM_MKL	Benign	0.14	N
LIST_S2	Benign	0.49	T;T;T
M_CAP	Benign	0.011	T
MetaRNN	Uncertain	0.53	D;D;D
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.39	N;.;.
PrimateAI	Benign	0.42	T
PROVEAN	Benign	0.77	N;N;.
REVEL	Uncertain	0.42
Sift	Benign	0.37	T;T;.
Sift4G	Benign	0.65	T;T;.
Polyphen		0.0	B;B;.
Vest4		0.059
MutPred		0.62		Gain of glycosylation at T290 (P = 0.0416);.;.;
MVP		0.83
MPC		0.056
ClinPred		0.25	T
GERP RS		2.0
Varity_R		0.18
gMVP		0.28

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs104893942; hg19: chr6-131904948;