rs34504481

chr6-131579250-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000045.4(ARG1):c.270C>T(p.Asn90=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0556 in 1,613,884 control chromosomes in the GnomAD database, including 2,726 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.042 (209 hom., cov: 32)
  • Exomes 𝑓: 0.057 (2517 hom.)
• Consequence: ARG1 NM_000045.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.961

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 Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 6-131579250-C-T is Benign according to our data. Variant chr6-131579250-C-T is described in ClinVar as [Benign]. Clinvar id is 136419.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-131579250-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.961 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0615 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ARG1	NM_000045.4	c.270C>T	p.Asn90=	synonymous_variant	3/8	ENST00000368087.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ARG1	ENST00000368087.8	c.270C>T	p.Asn90=	synonymous_variant	3/8	1	NM_000045.4	P3

Frequencies

GnomAD3 genomes AF: 0.0420 AC: 6386 AN: 151998 Hom.: 209 Cov.: 32

Gnomad AFR AF: 0.0105

Gnomad AMI AF: 0.0526

Gnomad AMR AF: 0.0317

Gnomad ASJ AF: 0.0559

Gnomad EAS AF: 0.000770

Gnomad SAS AF: 0.0579

Gnomad FIN AF: 0.0503

Gnomad MID AF: 0.0696

Gnomad NFE AF: 0.0631

Gnomad OTH AF: 0.0465

GnomAD3 exomes AF: 0.0474 AC: 11899 AN: 251102 Hom.: 342 AF XY: 0.0490 AC XY: 6651 AN XY: 135692

Gnomad AFR exome AF: 0.00917

Gnomad AMR exome AF: 0.0279

Gnomad ASJ exome AF: 0.0588

Gnomad EAS exome AF: 0.000218

Gnomad SAS exome AF: 0.0551

Gnomad FIN exome AF: 0.0490

Gnomad NFE exome AF: 0.0628

Gnomad OTH exome AF: 0.0505

GnomAD4 exome AF: 0.0570 AC: 83385 AN: 1461768 Hom.: 2517 Cov.: 31 AF XY: 0.0575 AC XY: 41832 AN XY: 727190

Gnomad4 AFR exome AF: 0.00827

Gnomad4 AMR exome AF: 0.0297

Gnomad4 ASJ exome AF: 0.0575

Gnomad4 EAS exome AF: 0.000202

Gnomad4 SAS exome AF: 0.0607

Gnomad4 FIN exome AF: 0.0504

Gnomad4 NFE exome AF: 0.0618

Gnomad4 OTH exome AF: 0.0534

GnomAD4 genome AF: 0.0419 AC: 6381 AN: 152116 Hom.: 209 Cov.: 32 AF XY: 0.0414 AC XY: 3076 AN XY: 74358

Gnomad4 AFR AF: 0.0105

Gnomad4 AMR AF: 0.0316

Gnomad4 ASJ AF: 0.0559

Gnomad4 EAS AF: 0.000772

Gnomad4 SAS AF: 0.0578

Gnomad4 FIN AF: 0.0503

Gnomad4 NFE AF: 0.0631

Gnomad4 OTH AF: 0.0455

Alfa AF: 0.0555 Hom.: 129

Bravo AF: 0.0396

Asia WGS AF: 0.0240 AC: 83 AN: 3476

EpiCase AF: 0.0652

EpiControl AF: 0.0658

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 10, 2014	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Arginase deficiency Benign:3

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Intellectual disability, autosomal recessive 18 Benign:1

Benign, no assertion criteria provided

clinical testing

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
Cadd	Benign	0.25
Dann	Benign	0.73

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: rs34504481; hg19: chr6-131900390; COSMIC: COSV51580774;