6-131577068-T-C

Variant names:

• chr6-131577068-T-C
• rs2246012
• NM_000045.4:c.130+333T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000045.4(ARG1):​c.130+333T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.171 in 152,136 control chromosomes in the GnomAD database, including 2,529 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.17 (2529 hom., cov: 32)
• Consequence: ARG1 NM_000045.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.21
• Publications: 44 publications found

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]

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

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.341 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ARG1	NM_000045.4	c.130+333T>C		intron_variant	Intron 2 of 7	ENST00000368087.8	NP_000036.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ARG1	ENST00000368087.8	c.130+333T>C		intron_variant	Intron 2 of 7	1	NM_000045.4	ENSP00000357066.3

Frequencies

GnomAD3 genomes AF: 0.171 AC: 25983 AN: 152018 Hom.: 2525 Cov.: 32

Gnomad AFR AF: 0.126

Gnomad AMI AF: 0.252

Gnomad AMR AF: 0.234

Gnomad ASJ AF: 0.0923

Gnomad EAS AF: 0.355

Gnomad SAS AF: 0.226

Gnomad FIN AF: 0.229

Gnomad MID AF: 0.0728

Gnomad NFE AF: 0.162

Gnomad OTH AF: 0.143

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.171 AC: 26003 AN: 152136 Hom.: 2529 Cov.: 32 AF XY: 0.178 AC XY: 13203 AN XY: 74368

African (AFR) AF: 0.126 AC: 5222 AN: 41512

American (AMR) AF: 0.235 AC: 3583 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.0923 AC: 320 AN: 3468

East Asian (EAS) AF: 0.355 AC: 1829 AN: 5154

South Asian (SAS) AF: 0.225 AC: 1087 AN: 4822

European-Finnish (FIN) AF: 0.229 AC: 2423 AN: 10586

Middle Eastern (MID) AF: 0.0782 AC: 23 AN: 294

European-Non Finnish (NFE) AF: 0.162 AC: 10987 AN: 68002

Other (OTH) AF: 0.142 AC: 299 AN: 2110

Alfa AF: 0.160 Hom.: 4470

Bravo AF: 0.170

Asia WGS AF: 0.216 AC: 752 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.34
DANN	Benign	0.22
PhyloP100		-1.2
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2246012; hg19: chr6-131898208;