chr6-131579250-C-A

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000045.4(ARG1):​c.270C>A​(p.Asn90Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. N90N) has been classified as Benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ARG1 NM_000045.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.961
• Publications: 0 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.09829283).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ARG1	NM_000045.4	c.270C>A	p.Asn90Lys	missense_variant	Exon 3 of 8	ENST00000368087.8	NP_000036.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ARG1	ENST00000368087.8	c.270C>A	p.Asn90Lys	missense_variant	Exon 3 of 8	1	NM_000045.4	ENSP00000357066.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Mar 03, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.270C>A (p.N90K) alteration is located in exon 3 (coding exon 3) of the ARG1 gene. This alteration results from a C to A substitution at nucleotide position 270, causing the asparagine (N) at amino acid position 90 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	0.0030
DANN	Benign	0.69
DEOGEN2	Benign	0.36	T;.;.
Eigen	Benign	-2.3
Eigen_PC	Benign	-2.4
FATHMM_MKL	Benign	0.055	N
LIST_S2	Benign	0.63	T;T;T
M_CAP	Benign	0.034	D
MetaRNN	Benign	0.098	T;T;T
MetaSVM	Benign	-0.89	T
MutationAssessor	Benign	-0.020	N;.;N
PhyloP100		-0.96
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-0.37	N;N;.
REVEL	Benign	0.24
Sift	Benign	0.92	T;T;.
Sift4G	Benign	0.80	T;T;.
Polyphen		0.0050	B;B;.
Vest4		0.23
MutPred		0.34		Gain of MoRF binding (P = 0.0323);.;Gain of MoRF binding (P = 0.0323);
MVP		0.59
MPC		0.082
ClinPred		0.053	T
GERP RS		-12
Varity_R		0.31
gMVP		0.28
Mutation Taster		=75/25	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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;