chr6-131576681-G-A

Variant names:

• chr6-131576681-G-A
• rs998513101
• NM_000045.4:c.76G>A

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM1 PM2

The NM_000045.4(ARG1):​c.76G>A​(p.Glu26Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000131 in 152,208 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/24 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: 𝑓 0.000013 (0 hom., cov: 32)
• Consequence: ARG1 NM_000045.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.894
• Publications: 1 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: Uncertain_significance. The variant received 4 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 10 uncertain in NM_000045.4
• PM2: Very rare variant in population databases, with high coverage

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.76G>A	p.Glu26Lys	missense	Exon 2 of 8	NP_000036.2
	ARG1	NM_001244438.2		c.76G>A	p.Glu26Lys	missense	Exon 2 of 8	NP_001231367.1	P05089-2
	ARG1	NM_001369020.1		c.76G>A	p.Glu26Lys	missense	Exon 2 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.76G>A	p.Glu26Lys	missense	Exon 2 of 8	ENSP00000357066.3	P05089-1
	ARG1	ENST00000356962.2	TSL:1	c.76G>A	p.Glu26Lys	missense	Exon 2 of 8	ENSP00000349446.2	P05089-2
	MED23	ENST00000354577.8	TSL:1	c.4096-2386C>T		intron	N/A	ENSP00000346588.4	Q9ULK4-3

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152208 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152208 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74352

African (AFR) AF: 0.0000483 AC: 2 AN: 41446

American (AMR) AF: 0.00 AC: 0 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5196

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68050

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Arginase deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	16
DANN	Benign	0.93
DEOGEN2	Benign	0.36	T
Eigen	Benign	-0.60
Eigen_PC	Benign	-0.41
FATHMM_MKL	Benign	0.59	D
LIST_S2	Benign	0.76	T
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.18	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	0.18	N
PhyloP100		0.89
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-0.42	N
REVEL	Benign	0.17
Sift	Benign	0.93	T
Sift4G	Benign	0.89	T
Polyphen		0.0	B
Vest4		0.15
MutPred		0.49		Gain of MoRF binding (P = 0.0152)
MVP		0.89
MPC		0.067
ClinPred		0.23	T
GERP RS		2.3
Varity_R		0.16
gMVP		0.58
Mutation Taster		=78/22	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.30		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.30		Position offset: -18

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs998513101; hg19: chr6-131897821;