Genetic Variant NDRG1:p.Ala370Asp (chr8-133238954-G-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_006096.4(NDRG1):c.1109C>A(p.Ala370Asp) variant causes a missense change. The variant allele was found at a frequency of 0.000000702 in 1,424,738 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A370V) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 7.0e-7 ( 0 hom. )

Consequence

NDRG1
NM_006096.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.62

Publications

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

NDRG1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.16001531).

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.1109C>A	p.Ala370Asp	missense	Exon 16 of 16	NP_006087.2
NDRG1	NM_001374844.1		c.1160C>A	p.Ala387Asp	missense	Exon 16 of 16	NP_001361773.1
NDRG1	NM_001135242.2		c.1109C>A	p.Ala370Asp	missense	Exon 16 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.1109C>A	p.Ala370Asp	missense	Exon 16 of 16	ENSP00000319977.8	Q92597-1
NDRG1	ENST00000522476.5	TSL:1	c.911C>A	p.Ala304Asp	missense	Exon 14 of 14	ENSP00000427894.1	Q92597-2
NDRG1	ENST00000414097.6	TSL:2	c.1109C>A	p.Ala370Asp	missense	Exon 16 of 16	ENSP00000404854.2	Q92597-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.02e-7

AC:

AN:

1424738

Hom.:

Cov.:

AF XY:

0.00000142

AC XY:

AN XY:

705020

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

33046

American (AMR)

AF:

0.00

AC:

AN:

38210

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25380

East Asian (EAS)

AF:

0.00

AC:

AN:

38222

South Asian (SAS)

AF:

0.00

AC:

AN:

81156

European-Finnish (FIN)

AF:

0.0000201

AC:

AN:

49746

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5558

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1094458

Other (OTH)

AF:

0.00

AC:

AN:

58962

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.225

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.18

BayesDel_noAF

Benign

-0.50

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.20

Eigen

Benign

0.022

Eigen_PC

Uncertain

0.23

FATHMM_MKL

Uncertain

0.92

LIST_S2

Benign

0.82

M_CAP

Benign

0.024

MetaRNN

Benign

0.16

MetaSVM

Benign

-0.99

MutationAssessor

Benign

0.90

PhyloP100

3.6

PrimateAI

Uncertain

0.58

PROVEAN

Benign

-0.69

REVEL

Benign

0.096

Sift

Uncertain

0.0090

Sift4G

Benign

0.095

Polyphen

0.054

Vest4

0.14

MutPred

0.087

Gain of relative solvent accessibility (P = 0.09)

MVP

0.67

MPC

0.48

ClinPred

0.62

GERP RS

5.5

Varity_R

0.17

gMVP

0.68

Mutation Taster

=68/32

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over