Genetic Variant NDRG1:p.Pro293Pro (chr8-133244367-C-T) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_006096.4(NDRG1):c.879G>A(p.Pro293Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000797 in 1,614,200 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. P293P) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0043 ( 6 hom., cov: 33)

Exomes 𝑓: 0.00043 ( 5 hom. )

Consequence

NDRG1
NM_006096.4 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: -5.65

Publications

1 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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.66).

BP6

Variant 8-133244367-C-T is Benign according to our data. Variant chr8-133244367-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 416508.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-5.65 with no splicing effect.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0043 (655/152350) while in subpopulation AFR AF = 0.015 (625/41584). AF 95% confidence interval is 0.0141. There are 6 homozygotes in GnomAd4. There are 306 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 6 AR gene

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	HGVSp	Effect	Exon Rank	Protein	UniProt
NDRG1	NM_006096.4	MANE Select	c.879G>A	p.Pro293Pro	synonymous	Exon 14 of 16	NP_006087.2
NDRG1	NM_001374844.1		c.930G>A	p.Pro310Pro	synonymous	Exon 14 of 16	NP_001361773.1
NDRG1	NM_001135242.2		c.879G>A	p.Pro293Pro	synonymous	Exon 14 of 16	NP_001128714.1	Q92597-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
NDRG1	ENST00000323851.13	TSL:1 MANE Select	c.879G>A	p.Pro293Pro	synonymous	Exon 14 of 16	ENSP00000319977.8	Q92597-1
NDRG1	ENST00000522476.5	TSL:1	c.681G>A	p.Pro227Pro	synonymous	Exon 12 of 14	ENSP00000427894.1	Q92597-2
NDRG1	ENST00000675568.1		c.92G>A	p.Arg31His	missense	Exon 2 of 2	ENSP00000501738.1	A0A6Q8PFB3

Frequencies

GnomAD3 genomes

AF:

0.00427

AC:

650

AN:

152232

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0150

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00105

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000588

Gnomad OTH

AF:

0.00430

GnomAD2 exomes

AF:

0.00117

AC:

295

AN:

251204

AF XY:

0.000847

show subpopulations

Gnomad AFR exome

AF:

0.0154

Gnomad AMR exome

AF:

0.000897

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000704

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.000432

AC:

632

AN:

1461850

Hom.:

Cov.:

AF XY:

0.000399

AC XY:

290

AN XY:

727216

show subpopulations

African (AFR)

AF:

0.0145

AC:

485

AN:

33480

American (AMR)

AF:

0.000917

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.0000383

AC:

AN:

26136

East Asian (EAS)

AF:

0.000101

AC:

AN:

39698

South Asian (SAS)

AF:

0.000139

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53390

Middle Eastern (MID)

AF:

0.000867

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000198

AC:

AN:

1112006

Other (OTH)

AF:

0.00103

AC:

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.463

Heterozygous variant carriers

119

159

199

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<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:

0.00430

AC:

655

AN:

152350

Hom.:

Cov.:

AF XY:

0.00411

AC XY:

306

AN XY:

74504

show subpopulations

African (AFR)

AF:

0.0150

AC:

625

AN:

41584

American (AMR)

AF:

0.00105

AC:

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.000193

AC:

AN:

5184

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000588

AC:

AN:

68030

Other (OTH)

AF:

0.00426

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

Heterozygous variant carriers

130

162

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<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:

0.00228

Hom.:

Bravo

AF:

0.00478

EpiCase

AF:

0.00

EpiControl

AF:

0.000178

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

Charcot-Marie-Tooth disease type 4D (2)

Charcot-Marie-Tooth disease (1)

Charcot-Marie-Tooth disease type 4 (1)

Inborn genetic diseases (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.66

CADD

Benign

1.0

(source)

DANN

Benign

0.84

PhyloP100

-5.7

RBP_binding_hub_radar

0.92

RBP_regulation_power_radar

2.6

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

Splicevardb

2.0

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

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