6-131578132-G-A

Variant names:

• chr6-131578132-G-A
• rs17657775
• NM_000045.4:c.131-979G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_000045.4(ARG1):​c.131-979G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0326 in 149,706 control chromosomes in the GnomAD database, including 110 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 0.033 (110 hom., cov: 30)
• Consequence: ARG1 NM_000045.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.900
• Publications: 2 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=-0.91).
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0326 (4881/149706) while in subpopulation AFR AF = 0.0514 (2083/40508). AF 95% confidence interval is 0.0496. There are 110 homozygotes in GnomAd4. There are 2398 alleles in the male GnomAd4 subpopulation. Median coverage is 30. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 110 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ARG1	NM_000045.4	c.131-979G>A		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.131-979G>A		intron_variant	Intron 2 of 7	1	NM_000045.4	ENSP00000357066.3

Frequencies

GnomAD3 genomes AF: 0.0326 AC: 4871 AN: 149604 Hom.: 110 Cov.: 30

Gnomad AFR AF: 0.0513

Gnomad AMI AF: 0.0252

Gnomad AMR AF: 0.0443

Gnomad ASJ AF: 0.0482

Gnomad EAS AF: 0.000196

Gnomad SAS AF: 0.0329

Gnomad FIN AF: 0.00767

Gnomad MID AF: 0.0654

Gnomad NFE AF: 0.0236

Gnomad OTH AF: 0.0472

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

GnomAD4 genome AF: 0.0326 AC: 4881 AN: 149706 Hom.: 110 Cov.: 30 AF XY: 0.0329 AC XY: 2398 AN XY: 72850

African (AFR) AF: 0.0514 AC: 2083 AN: 40508

American (AMR) AF: 0.0443 AC: 663 AN: 14974

Ashkenazi Jewish (ASJ) AF: 0.0482 AC: 167 AN: 3462

East Asian (EAS) AF: 0.000196 AC: 1 AN: 5094

South Asian (SAS) AF: 0.0332 AC: 157 AN: 4736

European-Finnish (FIN) AF: 0.00767 AC: 76 AN: 9908

Middle Eastern (MID) AF: 0.0634 AC: 18 AN: 284

European-Non Finnish (NFE) AF: 0.0236 AC: 1596 AN: 67754

Other (OTH) AF: 0.0468 AC: 97 AN: 2074

Alfa AF: 0.0309 Hom.: 11

Bravo AF: 0.0354

Asia WGS AF: 0.0180 AC: 63 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	6.2
DANN	Benign	0.50
PhyloP100		0.90
Mutation Taster		=100/0	polymorphism

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: rs17657775; hg19: chr6-131899272;