rs2233318
Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2BP4_StrongBS1_Supporting
The NM_006096.4(NDRG1):āc.122A>Gā(p.His41Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00075 in 1,614,140 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā ā ). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H41N) has been classified as Uncertain significance.
Frequency
Consequence
NM_006096.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -3 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
NDRG1 | NM_006096.4 | c.122A>G | p.His41Arg | missense_variant | 4/16 | ENST00000323851.13 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NDRG1 | ENST00000323851.13 | c.122A>G | p.His41Arg | missense_variant | 4/16 | 1 | NM_006096.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.000618 AC: 94AN: 152138Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.000624 AC: 157AN: 251490Hom.: 0 AF XY: 0.000728 AC XY: 99AN XY: 135920
GnomAD4 exome AF: 0.000764 AC: 1117AN: 1461884Hom.: 0 Cov.: 31 AF XY: 0.000798 AC XY: 580AN XY: 727244
GnomAD4 genome ? AF: 0.000617 AC: 94AN: 152256Hom.: 0 Cov.: 33 AF XY: 0.000551 AC XY: 41AN XY: 74448
ClinVar
Submissions by phenotype
not provided Uncertain:3
Uncertain significance, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Apr 01, 2018 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Aug 30, 2019 | In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Listed as a variant int he NCBI SNP database; however, this variant was not found in this study and no additional information was provided (Hunter et al., 2003); This variant is associated with the following publications: (PMID: 12872253, 32376792) - |
Uncertain significance, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | May 04, 2022 | BP4 - |
Charcot-Marie-Tooth disease type 4D Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | May 18, 2022 | - - |
Uncertain significance, no assertion criteria provided | clinical testing | Natera, Inc. | Jan 16, 2020 | - - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Athena Diagnostics | Oct 13, 2016 | - - |
Charcot-Marie-Tooth disease Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Molecular Genetics Laboratory, London Health Sciences Centre | - | - - |
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jul 19, 2022 | The p.H41R variant (also known as c.122A>G), located in coding exon 3 of the NDRG1 gene, results from an A to G substitution at nucleotide position 122. The histidine at codon 41 is replaced by arginine, an amino acid with highly similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Charcot-Marie-Tooth disease type 4 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Oct 13, 2022 | This sequence change replaces histidine, which is basic and polar, with arginine, which is basic and polar, at codon 41 of the NDRG1 protein (p.His41Arg). This variant is present in population databases (rs2233318, gnomAD 0.2%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with NDRG1-related conditions. ClinVar contains an entry for this variant (Variation ID: 245649). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt NDRG1 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at