8-133284281-C-T

Position:

chr8-133284281-C-T

Variant summary

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

The ENST00000323851.13(NDRG1):c.31G>A(p.Ala11Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00186 in 1,614,144 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 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 0.0014 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0019 ( 4 hom. )

Consequence

NDRG1
ENST00000323851.13 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6B:7

Conservation

PhyloP100: 3.33

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 Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.009936959).

BP6

Variant 8-133284281-C-T is Benign according to our data. Variant chr8-133284281-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 220934.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Uncertain_significance=6}.

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00137 (209/152258) while in subpopulation AMR AF= 0.00418 (64/15306). AF 95% confidence interval is 0.00336. There are 0 homozygotes in gnomad4. There are 97 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NDRG1	NM_006096.4 linkuse as main transcript	c.31G>A	p.Ala11Thr	missense_variant	2/16	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.31G>A	p.Ala11Thr	missense_variant	2/16	1	NM_006096.4	ENSP00000319977	P1	Q92597-1

Frequencies

GnomAD3 genomes

AF:

0.00137

AC:

209

AN:

152140

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000386

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00419

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00185

Gnomad OTH

AF:

0.00143

GnomAD3 exomes

AF:

0.00117

AC:

294

AN:

251476

Hom.:

AF XY:

0.000979

AC XY:

133

AN XY:

135910

show subpopulations

Gnomad AFR exome

AF:

0.000308

Gnomad AMR exome

AF:

0.00228

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.000139

Gnomad NFE exome

AF:

0.00171

Gnomad OTH exome

AF:

0.00195

GnomAD4 exome

AF:

0.00191

AC:

2797

AN:

1461886

Hom.:

Cov.:

AF XY:

0.00180

AC XY:

1307

AN XY:

727246

show subpopulations

Gnomad4 AFR exome

AF:

0.000508

Gnomad4 AMR exome

AF:

0.00239

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.0000562

Gnomad4 NFE exome

AF:

0.00233

Gnomad4 OTH exome

AF:

0.00134

GnomAD4 genome

AF:

0.00137

AC:

209

AN:

152258

Hom.:

Cov.:

AF XY:

0.00130

AC XY:

AN XY:

74438

show subpopulations

Gnomad4 AFR

AF:

0.000385

Gnomad4 AMR

AF:

0.00418

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00185

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.00144

Hom.:

Bravo

AF:

0.00175

TwinsUK

AF:

0.00324

AC:

ALSPAC

AF:

0.00311

AC:

ESP6500AA

AF:

0.000681

AC:

ESP6500EA

AF:

0.00174

AC:

ExAC

AF:

0.00102

AC:

124

EpiCase

AF:

0.00174

EpiControl

AF:

0.00184

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:6Benign:7

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2Benign:4

Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Nov 25, 2022	BP4 -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Nov 22, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 23, 2021	This variant is associated with the following publications: (PMID: 32376792) -

Charcot-Marie-Tooth disease type 4D

Uncertain:2

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. -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 22, 2023	The NDRG1 c.31G>A; p.Ala11Thr variant (rs145871479) is reported in the literature in a cohort of CMT patients (Volodarsky 2021), and is also reported in ClinVar (Variation ID: 220934). This variant is observed in the general population with an overall allele frequency of 0.1% (313/282870 alleles, including 1 homozygote) in the Genome Aggregation Database. The alanine at codon 11 is weakly conserved, but computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.153). Due to limited information, the clinical significance of this variant is uncertain at this time. References: Volodarsky M et al. Comprehensive genetic sequence and copy number analysis for Charcot-Marie-Tooth disease in a Canadian cohort of 2517 patients. J Med Genet. 2021 Apr;58(4):284-288. PMID: 32376792. -

Charcot-Marie-Tooth disease type 4

Benign:2

Likely benign, no assertion criteria provided	clinical testing	Natera, Inc.	Dec 27, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 20, 2023

The c.31G>A (p.A11T) alteration is located in exon 2 (coding exon 1) of the NDRG1 gene. This alteration results from a G to A substitution at nucleotide position 31, causing the alanine (A) at amino acid position 11 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

NDRG1-related disorder

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 21, 2023

The NDRG1 c.31G>A variant is predicted to result in the amino acid substitution p.Ala11Thr. This variant was reported in an individual with Charcot-Marie-Tooth disease (Table S2, Volodarsky et al 2021. PubMed ID: 32376792). This variant is reported in 0.23% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/8-134296524-C-T). Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Charcot-Marie-Tooth disease

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Molecular Genetics Laboratory, London Health Sciences Centre

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.083

BayesDel_addAF

Benign

-0.32

BayesDel_noAF

Benign

-0.24

CADD

Benign

DANN

Benign

0.84

DEOGEN2

Benign

0.12

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

Eigen

Benign

-0.10

Eigen_PC

Benign

-0.0051

FATHMM_MKL

Benign

0.73

LIST_S2

Uncertain

0.88

.;D;T;T;D;D;.;D;D;D;D

M_CAP

Benign

0.0093

MetaRNN

Benign

0.0099

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

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.53

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

MutationTaster

Benign

1.0

D;D;N;N;N;N;N

PrimateAI

Uncertain

0.56

PROVEAN

Benign

1.7

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

REVEL

Benign

0.15

Sift

Benign

1.0

T;T;D;T;T;T;T;T;T;T;T

Sift4G

Benign

1.0

T;T;D;T;.;T;T;T;.;.;T

Polyphen

0.027

B;B;D;.;.;.;.;.;.;.;.

Vest4

0.47

MVP

0.44

MPC

0.29

ClinPred

0.042

GERP RS

5.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.11

gMVP

0.39

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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