rs2781667

Variant names:

• chr6-131574004-C-T
• rs2781667
• ENST00000354577.8:c.*289G>A

Variant summary

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

The ENST00000354577.8(MED23):​c.*289G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.373 in 469,342 control chromosomes in the GnomAD database, including 36,876 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 0.44 (17149 hom., cov: 32)
  • Exomes 𝑓: 0.34 (19727 hom.)
• Consequence: MED23 ENST00000354577.8 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.432
• Publications: 44 publications found

Genes affected

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]

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 Gene-Disease associations (from GenCC):

• arginase deficiency

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Myriad Women’s Health, Orphanet, ClinGen, G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.707 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ARG1	NM_000045.4	c.57+665C>T		intron_variant	Intron 1 of 7	ENST00000368087.8	NP_000036.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ARG1	ENST00000368087.8	c.57+665C>T		intron_variant	Intron 1 of 7	1	NM_000045.4	ENSP00000357066.3

Frequencies

GnomAD3 genomes AF: 0.441 AC: 66920 AN: 151872 Hom.: 17101 Cov.: 32

Gnomad AFR AF: 0.713

Gnomad AMI AF: 0.337

Gnomad AMR AF: 0.453

Gnomad ASJ AF: 0.410

Gnomad EAS AF: 0.324

Gnomad SAS AF: 0.340

Gnomad FIN AF: 0.338

Gnomad MID AF: 0.418

Gnomad NFE AF: 0.308

Gnomad OTH AF: 0.410

GnomAD4 exome AF: 0.341 AC: 108128 AN: 317350 Hom.: 19727 Cov.: 2 AF XY: 0.339 AC XY: 56445 AN XY: 166302

African (AFR) AF: 0.707 AC: 7037 AN: 9948

American (AMR) AF: 0.460 AC: 6949 AN: 15096

Ashkenazi Jewish (ASJ) AF: 0.392 AC: 3820 AN: 9736

East Asian (EAS) AF: 0.326 AC: 7276 AN: 22330

South Asian (SAS) AF: 0.339 AC: 10493 AN: 30948

European-Finnish (FIN) AF: 0.336 AC: 6503 AN: 19362

Middle Eastern (MID) AF: 0.425 AC: 598 AN: 1408

European-Non Finnish (NFE) AF: 0.309 AC: 58641 AN: 189906

Other (OTH) AF: 0.366 AC: 6811 AN: 18616

GnomAD4 genome AF: 0.441 AC: 67030 AN: 151992 Hom.: 17149 Cov.: 32 AF XY: 0.441 AC XY: 32746 AN XY: 74304

African (AFR) AF: 0.713 AC: 29562 AN: 41436

American (AMR) AF: 0.453 AC: 6912 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.410 AC: 1423 AN: 3470

East Asian (EAS) AF: 0.325 AC: 1677 AN: 5166

South Asian (SAS) AF: 0.341 AC: 1643 AN: 4822

European-Finnish (FIN) AF: 0.338 AC: 3575 AN: 10566

Middle Eastern (MID) AF: 0.415 AC: 122 AN: 294

European-Non Finnish (NFE) AF: 0.308 AC: 20948 AN: 67956

Other (OTH) AF: 0.407 AC: 861 AN: 2114

Alfa AF: 0.364 Hom.: 14569

Bravo AF: 0.462

Asia WGS AF: 0.355 AC: 1237 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	2.3
DANN	Benign	0.47
PhyloP100		0.43
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
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: rs2781667; hg19: chr6-131895144; COSMIC: COSV51581737; COSMIC: COSV51581737;