rs2233328

Positions:

chr8-133259226-T-G

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_006096.4(NDRG1):c.331A>C(p.Met111Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0014 in 1,614,150 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0019 ( 2 hom., cov: 33)

Exomes 𝑓: 0.0013 ( 3 hom. )

Consequence

NDRG1
NM_006096.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:6

Conservation

PhyloP100: 0.412

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:

NDRG1 (HGNC:):

NDRG1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.010466516).

BP6

Variant 8-133259226-T-G is Benign according to our data. Variant chr8-133259226-T-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 188374.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Uncertain_significance=1, Benign=1}.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00186 (283/152288) while in subpopulation NFE AF= 0.00193 (131/68020). AF 95% confidence interval is 0.00166. There are 2 homozygotes in gnomad4. There are 171 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NDRG1	NM_006096.4 linkuse as main transcript	c.331A>C	p.Met111Leu	missense_variant	6/16	ENST00000323851.13	NP_006087.2	Q92597-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NDRG1	ENST00000323851.13 linkuse as main transcript	c.331A>C	p.Met111Leu	missense_variant	6/16	1	NM_006096.4	ENSP00000319977.8		Q92597-1

Frequencies

GnomAD3 genomes

AF:

0.00186

AC:

283

AN:

152170

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000965

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000393

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0133

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00193

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.00166

AC:

417

AN:

251480

Hom.:

AF XY:

0.00180

AC XY:

245

AN XY:

135918

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.000260

Gnomad ASJ exome

AF:

0.0000992

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0106

Gnomad NFE exome

AF:

0.00148

Gnomad OTH exome

AF:

0.00147

GnomAD4 exome

AF:

0.00135

AC:

1969

AN:

1461862

Hom.:

Cov.:

AF XY:

0.00139

AC XY:

1009

AN XY:

727228

show subpopulations

Gnomad4 AFR exome

AF:

0.000149

Gnomad4 AMR exome

AF:

0.000246

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00985

Gnomad4 NFE exome

AF:

0.00122

Gnomad4 OTH exome

AF:

0.00111

GnomAD4 genome

AF:

0.00186

AC:

283

AN:

152288

Hom.:

Cov.:

AF XY:

0.00230

AC XY:

171

AN XY:

74464

show subpopulations

Gnomad4 AFR

AF:

0.0000962

Gnomad4 AMR

AF:

0.000392

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0133

Gnomad4 NFE

AF:

0.00193

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.00129

Hom.:

Bravo

AF:

0.000623

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00234

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000930

AC:

ExAC

AF:

0.00140

AC:

170

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.000927

EpiControl

AF:

0.000948

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:6

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Charcot-Marie-Tooth disease type 4D

Uncertain:1Benign:1

Likely benign, no assertion criteria provided	clinical testing	Natera, Inc.	Jan 15, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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. -

not provided

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	NDRG1: BP4, BS1:Supporting -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 11, 2021	This variant is associated with the following publications: (PMID: 12872253) -

Charcot-Marie-Tooth disease

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Molecular Genetics Laboratory, London Health Sciences Centre

- -

Inborn genetic diseases

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 22, 2020

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Charcot-Marie-Tooth disease type 4

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 27, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.079

BayesDel_addAF

Benign

-0.48

BayesDel_noAF

Benign

-0.47

CADD

Benign

DANN

Benign

0.91

DEOGEN2

Benign

0.13

T;.;T;.;.;.;T;.;.;T;.;T

Eigen

Benign

-0.50

Eigen_PC

Benign

-0.34

FATHMM_MKL

Uncertain

0.84

LIST_S2

Benign

0.72

.;T;T;T;T;T;T;.;T;T;T;T

MetaRNN

Benign

0.010

T;T;T;T;T;T;T;T;T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.76

N;.;N;.;.;.;.;.;.;.;.;.

PrimateAI

Benign

0.37

PROVEAN

Benign

-1.4

N;N;N;N;N;N;N;N;N;N;N;N

REVEL

Benign

0.11

Sift

Benign

0.24

T;T;T;T;T;T;T;T;T;T;T;T

Sift4G

Benign

0.27

T;T;T;T;.;T;T;T;T;.;.;T

Polyphen

0.012

B;.;B;.;.;.;.;.;.;.;.;.

Vest4

0.17

MutPred

0.15

Loss of phosphorylation at Y110 (P = 0.0993);.;Loss of phosphorylation at Y110 (P = 0.0993);.;.;.;Loss of phosphorylation at Y110 (P = 0.0993);Loss of phosphorylation at Y110 (P = 0.0993);Loss of phosphorylation at Y110 (P = 0.0993);.;Loss of phosphorylation at Y110 (P = 0.0993);.;

MVP

0.21

MPC

0.28

ClinPred

0.017

GERP RS

1.7

Varity_R

0.19

gMVP

0.48

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