rs2781667

Positions:

• chr6-131574004-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000368087.8(ARG1):​c.57+665C>T variant causes a intron 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: ARG1 ENST00000368087.8 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.432

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]

ACMG classification

Verdict is Benign. Variant got -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/exons	MANE	Protein	UniProt
ARG1	NM_000045.4	c.57+665C>T		intron_variant		ENST00000368087.8	NP_000036.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ARG1	ENST00000368087.8	c.57+665C>T		intron_variant		1	NM_000045.4	ENSP00000357066	P3

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

Gnomad4 AFR exome AF: 0.707

Gnomad4 AMR exome AF: 0.460

Gnomad4 ASJ exome AF: 0.392

Gnomad4 EAS exome AF: 0.326

Gnomad4 SAS exome AF: 0.339

Gnomad4 FIN exome AF: 0.336

Gnomad4 NFE exome AF: 0.309

Gnomad4 OTH exome AF: 0.366

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

Gnomad4 AFR AF: 0.713

Gnomad4 AMR AF: 0.453

Gnomad4 ASJ AF: 0.410

Gnomad4 EAS AF: 0.325

Gnomad4 SAS AF: 0.341

Gnomad4 FIN AF: 0.338

Gnomad4 NFE AF: 0.308

Gnomad4 OTH AF: 0.407

Alfa AF: 0.347 Hom.: 9993

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
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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

Publications

LitVar

Other links and lift over

dbSNP: rs2781667; hg19: chr6-131895144; COSMIC: COSV51581737; COSMIC: COSV51581737;