chr8-133248705-A-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_006096.4(NDRG1):c.755+10T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0751 in 1,613,938 control chromosomes in the GnomAD database, including 6,378 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.065 ( 561 hom., cov: 33)

Exomes 𝑓: 0.076 ( 5817 hom. )

Consequence

NDRG1
NM_006096.4 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 0.685

Publications

8 publications found

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 Gene-Disease associations (from GenCC):

Charcot-Marie-Tooth disease type 4D
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), Illumina

NDRG1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.69).

BP6

Variant 8-133248705-A-G is Benign according to our data. Variant chr8-133248705-A-G is described in ClinVar as [Benign]. Clinvar id is 138433.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.272 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NDRG1	NM_006096.4 link	c.755+10T>C		intron_variant	Intron 11 of 15	ENST00000323851.13	NP_006087.2	Q92597-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NDRG1	ENST00000323851.13 link	c.755+10T>C		intron_variant	Intron 11 of 15	1	NM_006096.4	ENSP00000319977.8		Q92597-1

Frequencies

GnomAD3 genomes

AF:

0.0653

AC:

9924

AN:

152092

Hom.:

564

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0137

Gnomad AMI

AF:

0.0351

Gnomad AMR

AF:

0.0600

Gnomad ASJ

AF:

0.0375

Gnomad EAS

AF:

0.284

Gnomad SAS

AF:

0.100

Gnomad FIN

AF:

0.164

Gnomad MID

AF:

0.0475

Gnomad NFE

AF:

0.0654

Gnomad OTH

AF:

0.0587

GnomAD2 exomes

AF:

0.0947

AC:

23805

AN:

251342

AF XY:

0.0947

show subpopulations

Gnomad AFR exome

AF:

0.0112

Gnomad AMR exome

AF:

0.0948

Gnomad ASJ exome

AF:

0.0351

Gnomad EAS exome

AF:

0.298

Gnomad FIN exome

AF:

0.166

Gnomad NFE exome

AF:

0.0644

Gnomad OTH exome

AF:

0.0771

GnomAD4 exome

AF:

0.0762

AC:

111358

AN:

1461726

Hom.:

5817

Cov.:

AF XY:

0.0769

AC XY:

55899

AN XY:

727180

show subpopulations

African (AFR)

AF:

0.0102

AC:

342

AN:

33480

American (AMR)

AF:

0.0913

AC:

4083

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.0375

AC:

981

AN:

26136

East Asian (EAS)

AF:

0.280

AC:

11129

AN:

39698

South Asian (SAS)

AF:

0.104

AC:

8961

AN:

86254

European-Finnish (FIN)

AF:

0.159

AC:

8465

AN:

53390

Middle Eastern (MID)

AF:

0.0368

AC:

212

AN:

5766

European-Non Finnish (NFE)

AF:

0.0653

AC:

72594

AN:

1111890

Other (OTH)

AF:

0.0760

AC:

4591

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.469

Heterozygous variant carriers

5748

11496

17243

22991

28739

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2838

5676

8514

11352

14190

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0652

AC:

9920

AN:

152212

Hom.:

561

Cov.:

AF XY:

0.0720

AC XY:

5361

AN XY:

74420

show subpopulations

African (AFR)

AF:

0.0136

AC:

566

AN:

41550

American (AMR)

AF:

0.0602

AC:

920

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.0375

AC:

130

AN:

3470

East Asian (EAS)

AF:

0.284

AC:

1464

AN:

5162

South Asian (SAS)

AF:

0.100

AC:

482

AN:

4822

European-Finnish (FIN)

AF:

0.164

AC:

1740

AN:

10594

Middle Eastern (MID)

AF:

0.0408

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0655

AC:

4451

AN:

68000

Other (OTH)

AF:

0.0581

AC:

123

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

467

934

1401

1868

2335

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

114

228

342

456

570

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0587

Hom.:

423

Bravo

AF:

0.0577

Asia WGS

AF:

0.180

AC:

623

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Feb 28, 2014

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Jul 12, 2017

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Charcot-Marie-Tooth disease type 4D

Benign:2

Jul 10, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Charcot-Marie-Tooth disease type 4

Benign:2

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 16, 2020

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Charcot-Marie-Tooth disease

Benign:1

Molecular Genetics Laboratory, London Health Sciences Centre

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.69

CADD

Benign

9.4

(source)

DANN

Benign

0.78

PhyloP100

0.69

PromoterAI

0.019

Neutral

(source)

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over