NM_006096.4:c.980G>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_006096.4(NDRG1):​c.980G>T​(p.Arg327Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000635 in 1,573,648 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R327H) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)
Exomes 𝑓: 0.0000056 ( 0 hom. )

Consequence

NDRG1
NM_006096.4 missense

Scores

10
3
6

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.31

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: Orphanet, Labcorp Genetics (formerly Invitae), Illumina

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.4128321).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
NDRG1NM_006096.4 linkc.980G>T p.Arg327Leu missense_variant Exon 16 of 16 ENST00000323851.13 NP_006087.2 Q92597-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
NDRG1ENST00000323851.13 linkc.980G>T p.Arg327Leu missense_variant Exon 16 of 16 1 NM_006096.4 ENSP00000319977.8 Q92597-1

Frequencies

GnomAD3 genomes
AF:
0.0000131
AC:
2
AN:
152146
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000131
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:
0.00
Gnomad OTH
AF:
0.00
GnomAD2 exomes
AF:
0.0000168
AC:
3
AN:
178626
AF XY:
0.0000105
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.000115
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000563
AC:
8
AN:
1421384
Hom.:
0
Cov.:
30
AF XY:
0.00000569
AC XY:
4
AN XY:
703046
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
32934
American (AMR)
AF:
0.000133
AC:
5
AN:
37510
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
25382
East Asian (EAS)
AF:
0.00
AC:
0
AN:
38056
South Asian (SAS)
AF:
0.00
AC:
0
AN:
80940
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
50018
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5708
European-Non Finnish (NFE)
AF:
0.00000275
AC:
3
AN:
1091922
Other (OTH)
AF:
0.00
AC:
0
AN:
58914
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.481
Heterozygous variant carriers
0
1
2
3
4
5
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
2
4
6
8
10
<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:
0.0000131
AC:
2
AN:
152264
Hom.:
0
Cov.:
33
AF XY:
0.00
AC XY:
0
AN XY:
74450
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
41562
American (AMR)
AF:
0.000131
AC:
2
AN:
15296
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3472
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5164
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4830
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10610
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
294
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
68012
Other (OTH)
AF:
0.00
AC:
0
AN:
2112
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.450
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
Alfa
AF:
0.00
Hom.:
0
Bravo
AF:
0.0000302
ExAC
AF:
0.00000862
AC:
1

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Inborn genetic diseases Uncertain:1
Sep 24, 2024
Ambry Genetics
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

The c.980G>T (p.R327L) alteration is located in exon 16 (coding exon 15) of the NDRG1 gene. This alteration results from a G to T substitution at nucleotide position 980, causing the arginine (R) at amino acid position 327 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.99
BayesDel_addAF
Pathogenic
0.32
D
BayesDel_noAF
Pathogenic
0.22
CADD
Pathogenic
31
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.85
D;.;D;T;.;T
Eigen
Uncertain
0.68
Eigen_PC
Pathogenic
0.68
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Pathogenic
0.99
.;D;D;D;D;D
M_CAP
Benign
0.057
D
MetaRNN
Benign
0.41
T;T;T;T;T;T
MetaSVM
Benign
-0.57
T
MutationAssessor
Benign
1.8
L;.;L;.;.;.
PhyloP100
7.3
PrimateAI
Pathogenic
0.79
T
PROVEAN
Pathogenic
-6.2
D;D;D;D;D;D
REVEL
Benign
0.28
Sift
Uncertain
0.0030
D;D;D;D;D;D
Sift4G
Pathogenic
0.0010
D;D;D;D;D;D
Polyphen
0.98
D;.;D;D;.;.
Vest4
0.76
MutPred
0.33
Loss of methylation at R327 (P = 0.0593);.;Loss of methylation at R327 (P = 0.0593);.;.;.;
MVP
0.75
MPC
0.79
ClinPred
0.99
D
GERP RS
5.0
Varity_R
0.71
gMVP
0.85
Mutation Taster
=20/80
disease causing

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

Other links and lift over

dbSNP: rs565705964; hg19: chr8-134251326; API