rs1064794165

Positions:

chr6-131582620-G-C

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_000045.4(ARG1):c.466-1G>C variant causes a splice acceptor change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000806 in 1,612,280 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000082 ( 0 hom. )

Consequence

ARG1
NM_000045.4 splice_acceptor

Scores

Splicing: ADA: 1.000

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:6

Conservation

PhyloP100: 9.68

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 ACMG points.

PVS1

Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, Cryptic splice site detected, with MaxEntScore 4.2, offset of 16, new splice context is: ttacattcccgatgtgccAGgat. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 6-131582620-G-C is Pathogenic according to our data. Variant chr6-131582620-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 419876.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ARG1	NM_000045.4 linkuse as main transcript	c.466-1G>C		splice_acceptor_variant		ENST00000368087.8	NP_000036.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ARG1	ENST00000368087.8 linkuse as main transcript	c.466-1G>C		splice_acceptor_variant		1	NM_000045.4	ENSP00000357066	P3	P05089-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152152

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000279

AC:

AN:

251208

Hom.:

AF XY:

0.0000221

AC XY:

AN XY:

135762

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000202

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000822

AC:

AN:

1460128

Hom.:

Cov.:

AF XY:

0.00000826

AC XY:

AN XY:

726550

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000268

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:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152152

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74322

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000655

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000227

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Arginase deficiency

Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Centogene AG - the Rare Disease Company	Jun 25, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Nov 01, 2021	NM_000045.3(ARG1):c.466-1G>C is a canonical splice variant classified as pathogenic in the context of argininemia. c.466-1G>C has been observed in cases with relevant disease (PMID: 27038030, 26169240, 21802329). Functional assessments of this variant are available in the literature (PMID: 26169240). c.466-1G>C has been observed in population frequency databases (gnomAD: AMR 0.02%). In summary, NM_000045.3(ARG1):c.466-1G>C is a canonical splice variant in a gene where loss of function is a known mechanism of disease, is predicted to disrupt protein function, and has been observed more frequently in cases with the relevant disease than in healthy populations. Please note: this variant was assessed in the context of healthy population screening. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Feb 13, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 09, 2024	This sequence change affects an acceptor splice site in intron 4 of the ARG1 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in ARG1 are known to be pathogenic (PMID: 7649538, 12052859). This variant is present in population databases (no rsID available, gnomAD 0.03%). Disruption of this splice site has been observed in individual(s) with clinical features of ARG1-related conditions (PMID: 21802329, 26169240). ClinVar contains an entry for this variant (Variation ID: 419876). Studies have shown that disruption of this splice site alters ARG1 gene expression (PMID: 26169240). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jul 01, 2022

Canonical splice site variant in a gene for which loss-of-function is a known mechanism of disease; Published functional studies demonstrate that this variant leads to an aberrant transcript retaining intronic sequences (Villegas-Ruiz et al., 2015); This variant is associated with the following publications: (PMID: 27038030, 21802329, 26169240, 26467175, 29726057, 32778825) -

ARG1-related disorder

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 11, 2024

The ARG1 c.466-1G>C variant is predicted to disrupt the AG splice acceptor site and interfere with normal splicing. This variant was seen homozygous in two patients with autosomal recessive ARG1-related disease (Patient 6, Table 1, Jain-Ghai et al. 2011. PubMed ID: 21802329, Villegas-Ruiz et al. 2015. PubMed ID: 26169240). This variant is reported in 0.023% of alleles in individuals of Latino descent in gnomAD. Studies have shown that disruption of this splice site alters ARG1 gene expression (Villegas-Ruiz et al. 2015. PubMed ID: 26169240). This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.43

BayesDel_noAF

Uncertain

0.030

CADD

Pathogenic

DANN

Uncertain

0.99

Eigen

Pathogenic

0.96

Eigen_PC

Pathogenic

0.75

FATHMM_MKL

Pathogenic

1.0

MutationTaster

Benign

1.0

D;D;D;D

GERP RS

4.9

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.93

SpliceAI score (max)

0.83

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.57

Position offset: -50

DS_AL_spliceai

0.83

Position offset: 1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over