rs146613168

Positions:

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM2BP4_ModerateBS1_Supporting

The NM_006096.4(NDRG1):c.1027C>T(p.Arg343Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000125 in 1,596,878 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00018 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00012 ( 0 hom. )

Consequence

NDRG1
NM_006096.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:7

Conservation

PhyloP100: 2.96

Variant links:

Genes affected

NDRG1 (HGNC:7679): (N-myc downstream regulated 1) This gene is a member of the N-myc downregulated gene family which belongs to the alpha/beta hydrolase superfamily. The protein encoded by this gene is a cytoplasmic protein involved in stress responses, hormone responses, cell growth, and differentiation. The encoded protein is necessary for p53-mediated caspase activation and apoptosis. Mutations in this gene are a cause of Charcot-Marie-Tooth disease type 4D, and expression of this gene may be a prognostic indicator for several types of cancer. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, May 2012]

NDRG1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.21532467).

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.000184 (28/152228) while in subpopulation AMR AF= 0.000327 (5/15276). AF 95% confidence interval is 0.000171. There are 0 homozygotes in gnomad4. There are 12 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NDRG1	NM_006096.4 linkuse as main transcript	c.1027C>T	p.Arg343Cys	missense_variant	16/16	ENST00000323851.13	NP_006087.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NDRG1	ENST00000323851.13 linkuse as main transcript	c.1027C>T	p.Arg343Cys	missense_variant	16/16	1	NM_006096.4	ENSP00000319977	P1	Q92597-1

Frequencies

GnomAD3 genomes

AF:

0.000184

AC:

AN:

152110

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000328

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000942

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000265

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000153

AC:

AN:

215252

Hom.:

AF XY:

0.000163

AC XY:

AN XY:

116288

show subpopulations

Gnomad AFR exome

AF:

0.0000771

Gnomad AMR exome

AF:

0.000131

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000616

Gnomad SAS exome

AF:

0.000111

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000249

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000118

AC:

171

AN:

1444650

Hom.:

Cov.:

AF XY:

0.000133

AC XY:

AN XY:

716730

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000144

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000256

Gnomad4 SAS exome

AF:

0.0000481

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000140

Gnomad4 OTH exome

AF:

0.0000837

GnomAD4 genome

AF:

0.000184

AC:

AN:

152228

Hom.:

Cov.:

AF XY:

0.000161

AC XY:

AN XY:

74424

show subpopulations

Gnomad4 AFR

AF:

0.0000722

Gnomad4 AMR

AF:

0.000327

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0000942

Gnomad4 NFE

AF:

0.000265

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.000149

Hom.:

Bravo

AF:

0.000166

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000353

AC:

ExAC

AF:

0.000159

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	May 05, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Apr 17, 2023	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Charcot-Marie-Tooth disease type 4D

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Apr 23, 2021	The NDRG1 c.1027C>T, p.Arg343Cys variant (rs146613168), to our knowledge, has not been reported in the medical literature; however, this variant is listed in the ClinVar database (Variation ID: 362031). This variant is found in the general population with an overall allele frequency of 0.015% (36/246,612 alleles) in the Genome Aggregation Database. The arginine at codon 343 is highly conserved, but computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.249). Based on the available information, the clinical significance of this variant is uncertain. -

Charcot-Marie-Tooth disease type 4

Uncertain:2

Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Dec 17, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 01, 2022	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 343 of the NDRG1 protein (p.Arg343Cys). This variant is present in population databases (rs146613168, gnomAD 0.02%). 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: 362031). 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 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. -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 15, 2022

The c.1027C>T (p.R343C) alteration is located in exon 16 (coding exon 15) of the NDRG1 gene. This alteration results from a C to T substitution at nucleotide position 1027, causing the arginine (R) at amino acid position 343 to be replaced by a cysteine (C). 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

Pathogenic

0.68

BayesDel_addAF

Benign

-0.081

BayesDel_noAF

Uncertain

-0.060

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.87

D;.;D;T;.;T

Eigen

Uncertain

0.61

Eigen_PC

Uncertain

0.60

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.95

.;D;D;D;D;D

M_CAP

Benign

0.035

MetaRNN

Benign

0.22

T;T;T;T;T;T

MetaSVM

Benign

-0.64

MutationAssessor

Benign

1.4

L;.;L;.;.;.

MutationTaster

Benign

1.0

D;D;D;D;D;D;D

PrimateAI

Uncertain

0.65

PROVEAN

Pathogenic

-4.5

D;D;D;D;D;D

REVEL

Benign

0.25

Sift

Pathogenic

0.0

D;D;D;D;D;D

Sift4G

Pathogenic

0.0

D;D;D;D;D;D

Polyphen

1.0

D;.;D;D;.;.

Vest4

0.63

MVP

0.76

MPC

1.2

ClinPred

0.30

GERP RS

4.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.7

Varity_R

0.46

gMVP

0.64

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over