6-131583579-C-T

Variant names:

• chr6-131583579-C-T
• rs17599586
• NM_000045.4:c.802+88C>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_000045.4(ARG1):​c.802+88C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.117 in 1,561,086 control chromosomes in the GnomAD database, including 11,387 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.11 (1017 hom., cov: 32)
  • Exomes 𝑓: 0.12 (10370 hom.)
• Consequence: ARG1 NM_000045.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.80
• Publications: 16 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.96).
• BP6: Variant 6-131583579-C-T is Benign according to our data. Variant chr6-131583579-C-T is described in ClinVar as Benign. ClinVar VariationId is 1292140.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.122 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ARG1	NM_000045.4	c.802+88C>T		intron_variant	Intron 7 of 7	ENST00000368087.8	NP_000036.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ARG1	ENST00000368087.8	c.802+88C>T		intron_variant	Intron 7 of 7	1	NM_000045.4	ENSP00000357066.3

Frequencies

GnomAD3 genomes AF: 0.111 AC: 16873 AN: 152130 Hom.: 1012 Cov.: 32

Gnomad AFR AF: 0.111

Gnomad AMI AF: 0.136

Gnomad AMR AF: 0.0803

Gnomad ASJ AF: 0.193

Gnomad EAS AF: 0.00789

Gnomad SAS AF: 0.0968

Gnomad FIN AF: 0.0947

Gnomad MID AF: 0.199

Gnomad NFE AF: 0.124

Gnomad OTH AF: 0.109

GnomAD4 exome AF: 0.118 AC: 166045 AN: 1408838 Hom.: 10370 Cov.: 26 AF XY: 0.118 AC XY: 82893 AN XY: 702410

African (AFR) AF: 0.119 AC: 3731 AN: 31386

American (AMR) AF: 0.0613 AC: 2655 AN: 43306

Ashkenazi Jewish (ASJ) AF: 0.200 AC: 5112 AN: 25618

East Asian (EAS) AF: 0.00802 AC: 303 AN: 37758

South Asian (SAS) AF: 0.110 AC: 9150 AN: 83366

European-Finnish (FIN) AF: 0.102 AC: 5357 AN: 52742

Middle Eastern (MID) AF: 0.205 AC: 1126 AN: 5490

European-Non Finnish (NFE) AF: 0.123 AC: 131390 AN: 1070654

Other (OTH) AF: 0.123 AC: 7221 AN: 58518

GnomAD4 genome AF: 0.111 AC: 16901 AN: 152248 Hom.: 1017 Cov.: 32 AF XY: 0.109 AC XY: 8138 AN XY: 74448

African (AFR) AF: 0.111 AC: 4619 AN: 41522

American (AMR) AF: 0.0801 AC: 1225 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.193 AC: 668 AN: 3470

East Asian (EAS) AF: 0.00791 AC: 41 AN: 5184

South Asian (SAS) AF: 0.0986 AC: 476 AN: 4830

European-Finnish (FIN) AF: 0.0947 AC: 1004 AN: 10606

Middle Eastern (MID) AF: 0.194 AC: 57 AN: 294

European-Non Finnish (NFE) AF: 0.124 AC: 8458 AN: 68020

Other (OTH) AF: 0.108 AC: 229 AN: 2116

Alfa AF: 0.123 Hom.: 1864

Bravo AF: 0.111

Asia WGS AF: 0.0510 AC: 179 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Jun 23, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	0.0020
DANN	Benign	0.65
PhyloP100		-1.8
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: rs17599586; hg19: chr6-131904719;