rs757959356

chr6-131579192-G-Achr6-131579192-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_000045.4(ARG1):c.212G>A(p.Arg71Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00000274 in 1,461,836 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R71T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: ARG1 NM_000045.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.01

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ARG1	NM_000045.4	c.212G>A	p.Arg71Lys	missense_variant	3/8	ENST00000368087.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ARG1	ENST00000368087.8	c.212G>A	p.Arg71Lys	missense_variant	3/8	1	NM_000045.4	P3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000119 AC: 3 AN: 251324 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135838

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461836 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 727222

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000434 Hom.: 0

ExAC AF: 0.0000165 AC: 2

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Pathogenic	0.15
Cadd	Uncertain	24
Dann	Uncertain	0.99
DEOGEN2	Uncertain	0.56	D;.;.
Eigen	Benign	0.18
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.92	D;D;D
M_CAP	Uncertain	0.15	D
MetaRNN	Uncertain	0.57	D;D;D
MetaSVM	Uncertain	0.58	D
MutationAssessor	Benign	1.5	L;.;L
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-1.9	N;N;.
REVEL	Uncertain	0.32
Sift	Benign	0.067	T;T;.
Sift4G	Benign	0.20	T;T;.
Polyphen		0.27	B;P;.
Vest4		0.37
MutPred		0.41		Gain of ubiquitination at R71 (P = 0.0408);.;Gain of ubiquitination at R71 (P = 0.0408);
MVP		0.99
MPC		0.38
ClinPred		0.86	D
GERP RS		5.3
Varity_R		0.71
gMVP		0.53

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: rs757959356; hg19: chr6-131900332;