chr8-133280273-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.64-6T>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.567 in 1,612,932 control chromosomes in the GnomAD database, including 265,351 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.64 ( 32790 hom., cov: 32)

Exomes 𝑓: 0.56 ( 232561 hom. )

Consequence

NDRG1
NM_006096.4 splice_region, intron

Scores

Splicing: ADA: 0.000008000

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:13

Conservation

PhyloP100: 0.573

Publications

16 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: Illumina, Labcorp Genetics (formerly Invitae), Orphanet

NDRG1 links:

Genome browser will be placed here

new If you want to explore the variant's impact on the transcript NM_006096.4, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

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=-0.73).

BP6

Variant 8-133280273-A-G is Benign according to our data. Variant chr8-133280273-A-G is described in ClinVar as Benign. ClinVar VariationId is 259916.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.855 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006096.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
NDRG1	NM_006096.4	MANE Select	c.64-6T>C	splice_region intron	N/A	NP_006087.2
NDRG1	NM_001374844.1		c.64-6T>C	splice_region intron	N/A	NP_001361773.1
NDRG1	NM_001135242.2		c.64-6T>C	splice_region intron	N/A	NP_001128714.1	Q92597-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
NDRG1	ENST00000323851.13	TSL:1 MANE Select	c.64-6T>C	splice_region intron	N/A	ENSP00000319977.8	Q92597-1
NDRG1	ENST00000522476.5	TSL:1	c.-99-15621T>C	intron	N/A	ENSP00000427894.1	Q92597-2
NDRG1	ENST00000414097.6	TSL:2	c.64-6T>C	splice_region intron	N/A	ENSP00000404854.2	Q92597-1

Frequencies

GnomAD3 genomes

AF:

0.640

AC:

97248

AN:

151950

Hom.:

32741

Cov.:

show subpopulations

Gnomad AFR

AF:

0.862

Gnomad AMI

AF:

0.499

Gnomad AMR

AF:

0.534

Gnomad ASJ

AF:

0.641

Gnomad EAS

AF:

0.463

Gnomad SAS

AF:

0.410

Gnomad FIN

AF:

0.579

Gnomad MID

AF:

0.649

Gnomad NFE

AF:

0.570

Gnomad OTH

AF:

0.648

GnomAD2 exomes

AF:

0.556

AC:

139553

AN:

251082

AF XY:

0.549

show subpopulations

Gnomad AFR exome

AF:

0.870

Gnomad AMR exome

AF:

0.469

Gnomad ASJ exome

AF:

0.635

Gnomad EAS exome

AF:

0.465

Gnomad FIN exome

AF:

0.577

Gnomad NFE exome

AF:

0.572

Gnomad OTH exome

AF:

0.577

GnomAD4 exome

AF:

0.560

AC:

817722

AN:

1460864

Hom.:

232561

Cov.:

AF XY:

0.555

AC XY:

403631

AN XY:

726762

show subpopulations

African (AFR)

AF:

0.879

AC:

29434

AN:

33468

American (AMR)

AF:

0.478

AC:

21357

AN:

44700

Ashkenazi Jewish (ASJ)

AF:

0.643

AC:

16794

AN:

26128

East Asian (EAS)

AF:

0.468

AC:

18580

AN:

39686

South Asian (SAS)

AF:

0.438

AC:

37811

AN:

86238

European-Finnish (FIN)

AF:

0.580

AC:

30942

AN:

53386

Middle Eastern (MID)

AF:

0.641

AC:

3696

AN:

5766

European-Non Finnish (NFE)

AF:

0.562

AC:

623959

AN:

1111140

Other (OTH)

AF:

0.582

AC:

35149

AN:

60352

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.470

Heterozygous variant carriers

17376

34752

52129

69505

86881

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

17414

34828

52242

69656

87070

<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:

0.640

AC:

97347

AN:

152068

Hom.:

32790

Cov.:

AF XY:

0.632

AC XY:

46944

AN XY:

74330

show subpopulations

African (AFR)

AF:

0.862

AC:

35777

AN:

41500

American (AMR)

AF:

0.534

AC:

8162

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.641

AC:

2222

AN:

3468

East Asian (EAS)

AF:

0.463

AC:

2391

AN:

5164

South Asian (SAS)

AF:

0.409

AC:

1974

AN:

4822

European-Finnish (FIN)

AF:

0.579

AC:

6107

AN:

10556

Middle Eastern (MID)

AF:

0.646

AC:

190

AN:

294

European-Non Finnish (NFE)

AF:

0.570

AC:

38708

AN:

67956

Other (OTH)

AF:

0.645

AC:

1361

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1645

3290

4935

6580

8225

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

754

1508

2262

3016

3770

<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:

0.599

Hom.:

29466

Bravo

AF:

0.653

Asia WGS

AF:

0.507

AC:

1765

AN:

3478

EpiCase

AF:

0.575

EpiControl

AF:

0.575

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (5)

Charcot-Marie-Tooth disease type 4D (3)

Charcot-Marie-Tooth disease type 4 (2)

not provided (2)

Charcot-Marie-Tooth disease (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.73

CADD

Benign

(source)

DANN

Benign

0.49

PhyloP100

0.57

PromoterAI

-0.0047

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Mutation Taster

=99/1

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.0000080

dbscSNV1_RF

Benign

0.0

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over