6-131579250-C-T

Variant names:

• chr6-131579250-C-T
• rs34504481
• NM_000045.4:c.270C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000045.4(ARG1):​c.270C>T​(p.Asn90Asn) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0556 in 1,613,884 control chromosomes in the GnomAD database, including 2,726 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.042 (209 hom., cov: 32)
  • Exomes 𝑓: 0.057 (2517 hom.)
• Consequence: ARG1 NM_000045.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.961
• Publications: 9 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: Labcorp Genetics (formerly Invitae), Ambry Genetics, 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 6-131579250-C-T is Benign according to our data. Variant chr6-131579250-C-T is described in ClinVar as Benign. ClinVar VariationId is 136419.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.961 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0615 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000045.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARG1	NM_000045.4	MANE Select	c.270C>T	p.Asn90Asn	synonymous	Exon 3 of 8	NP_000036.2
	ARG1	NM_001244438.2		c.294C>T	p.Asn98Asn	synonymous	Exon 3 of 8	NP_001231367.1	P05089-2
	ARG1	NM_001369020.1		c.270C>T	p.Asn90Asn	synonymous	Exon 3 of 6	NP_001355949.1	A0A5F9ZH78

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARG1	ENST00000368087.8	TSL:1 MANE Select	c.270C>T	p.Asn90Asn	synonymous	Exon 3 of 8	ENSP00000357066.3	P05089-1
	ARG1	ENST00000356962.2	TSL:1	c.294C>T	p.Asn98Asn	synonymous	Exon 3 of 8	ENSP00000349446.2	P05089-2
	MED23	ENST00000354577.8	TSL:1	c.4096-4955G>A		intron	N/A	ENSP00000346588.4	Q9ULK4-3

Frequencies

GnomAD3 genomes AF: 0.0420 AC: 6386 AN: 151998 Hom.: 209 Cov.: 32

Gnomad AFR AF: 0.0105

Gnomad AMI AF: 0.0526

Gnomad AMR AF: 0.0317

Gnomad ASJ AF: 0.0559

Gnomad EAS AF: 0.000770

Gnomad SAS AF: 0.0579

Gnomad FIN AF: 0.0503

Gnomad MID AF: 0.0696

Gnomad NFE AF: 0.0631

Gnomad OTH AF: 0.0465

GnomAD2 exomes AF: 0.0474 AC: 11899 AN: 251102 AF XY: 0.0490

Gnomad AFR exome AF: 0.00917

Gnomad AMR exome AF: 0.0279

Gnomad ASJ exome AF: 0.0588

Gnomad EAS exome AF: 0.000218

Gnomad FIN exome AF: 0.0490

Gnomad NFE exome AF: 0.0628

Gnomad OTH exome AF: 0.0505

GnomAD4 exome AF: 0.0570 AC: 83385 AN: 1461768 Hom.: 2517 Cov.: 31 AF XY: 0.0575 AC XY: 41832 AN XY: 727190

African (AFR) AF: 0.00827 AC: 277 AN: 33480

American (AMR) AF: 0.0297 AC: 1329 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.0575 AC: 1502 AN: 26132

East Asian (EAS) AF: 0.000202 AC: 8 AN: 39696

South Asian (SAS) AF: 0.0607 AC: 5234 AN: 86244

European-Finnish (FIN) AF: 0.0504 AC: 2692 AN: 53396

Middle Eastern (MID) AF: 0.0612 AC: 353 AN: 5768

European-Non Finnish (NFE) AF: 0.0618 AC: 68765 AN: 1111944

Other (OTH) AF: 0.0534 AC: 3225 AN: 60392

GnomAD4 genome AF: 0.0419 AC: 6381 AN: 152116 Hom.: 209 Cov.: 32 AF XY: 0.0414 AC XY: 3076 AN XY: 74358

African (AFR) AF: 0.0105 AC: 436 AN: 41502

American (AMR) AF: 0.0316 AC: 483 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.0559 AC: 194 AN: 3470

East Asian (EAS) AF: 0.000772 AC: 4 AN: 5180

South Asian (SAS) AF: 0.0578 AC: 278 AN: 4812

European-Finnish (FIN) AF: 0.0503 AC: 531 AN: 10566

Middle Eastern (MID) AF: 0.0680 AC: 20 AN: 294

European-Non Finnish (NFE) AF: 0.0631 AC: 4291 AN: 67996

Other (OTH) AF: 0.0455 AC: 96 AN: 2108

Alfa AF: 0.0489 Hom.: 188

Bravo AF: 0.0396

Asia WGS AF: 0.0240 AC: 83 AN: 3476

EpiCase AF: 0.0652

EpiControl AF: 0.0658

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Arginase deficiency (3)
-	-	3	not specified (3)
-	-	1	Intellectual disability, autosomal recessive 18 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.25
DANN	Benign	0.73
PhyloP100		-0.96
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs34504481; hg19: chr6-131900390; COSMIC: COSV51580774;