6-131579250-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_000045.4(ARG1):c.270C>T(p.Asn90Asn) 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

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: -0.961

Publications

9 publications found

Variant links:

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]

ARG1 links:

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]

MED23 Gene-Disease associations (from GenCC):

intellectual disability, autosomal recessive 18
Inheritance: AR Classification: STRONG, MODERATE, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
syndromic intellectual disability
Inheritance: AR Classification: MODERATE Submitted by: ClinGen
autosomal recessive non-syndromic intellectual disability
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

MED23 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 VariationId is 136419.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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 rank	MANE	Protein	UniProt
ARG1	NM_000045.4 link	c.270C>T	p.Asn90Asn	synonymous_variant	Exon 3 of 8	ENST00000368087.8	NP_000036.2	P05089-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ARG1	ENST00000368087.8 link	c.270C>T	p.Asn90Asn	synonymous_variant	Exon 3 of 8	1	NM_000045.4	ENSP00000357066.3		P05089-1

Frequencies

GnomAD3 genomes

AF:

0.0420

AC:

6386

AN:

151998

Hom.:

209

Cov.:

show subpopulations

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

GnomAD2 exomes

AF:

0.0474

AC:

11899

AN:

251102

AF XY:

0.0490

show subpopulations

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 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.:

AF XY:

0.0575

AC XY:

41832

AN XY:

727190

show subpopulations

African (AFR)

AF:

0.00827

AC:

277

AN:

33480

American (AMR)

AF:

0.0297

AC:

1329

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.0575

AC:

1502

AN:

26132

East Asian (EAS)

AF:

0.000202

AC:

AN:

39696

South Asian (SAS)

AF:

0.0607

AC:

5234

AN:

86244

European-Finnish (FIN)

AF:

0.0504

AC:

2692

AN:

53396

Middle Eastern (MID)

AF:

0.0612

AC:

353

AN:

5768

European-Non Finnish (NFE)

AF:

0.0618

AC:

68765

AN:

1111944

Other (OTH)

AF:

0.0534

AC:

3225

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

4319

8638

12957

17276

21595

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2508

5016

7524

10032

12540

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0419

AC:

6381

AN:

152116

Hom.:

209

Cov.:

AF XY:

0.0414

AC XY:

3076

AN XY:

74358

show subpopulations

African (AFR)

AF:

0.0105

AC:

436

AN:

41502

American (AMR)

AF:

0.0316

AC:

483

AN:

15276

Ashkenazi Jewish (ASJ)

AF:

0.0559

AC:

194

AN:

3470

East Asian (EAS)

AF:

0.000772

AC:

AN:

5180

South Asian (SAS)

AF:

0.0578

AC:

278

AN:

4812

European-Finnish (FIN)

AF:

0.0503

AC:

531

AN:

10566

Middle Eastern (MID)

AF:

0.0680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0631

AC:

4291

AN:

67996

Other (OTH)

AF:

0.0455

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

298

596

894

1192

1490

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

156

234

312

390

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0489

Hom.:

188

Bravo

AF:

0.0396

Asia WGS

AF:

0.0240

AC:

AN:

3476

EpiCase

AF:

0.0652

EpiControl

AF:

0.0658

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 10, 2014

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Arginase deficiency

Benign:3

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Intellectual disability, autosomal recessive 18

Benign:1

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.88

CADD

Benign

0.25

(source)

DANN

Benign

0.73

PhyloP100

-0.96

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over