rs145871479

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The ENST00000323851.13(NDRG1):​c.31G>A​(p.Ala11Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00186 in 1,614,144 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0014 ( 0 hom., cov: 33)
Exomes 𝑓: 0.0019 ( 4 hom. )

Consequence

NDRG1
ENST00000323851.13 missense

Scores

2
17

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6B:7

Conservation

PhyloP100: 3.33
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]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.009936959).
BP6
Variant 8-133284281-C-T is Benign according to our data. Variant chr8-133284281-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 220934.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Uncertain_significance=6}.
BS1
Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00137 (209/152258) while in subpopulation AMR AF= 0.00418 (64/15306). AF 95% confidence interval is 0.00336. There are 0 homozygotes in gnomad4. There are 97 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
BS2
High Homozygotes in GnomAdExome4 at 4 AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
NDRG1NM_006096.4 linkuse as main transcriptc.31G>A p.Ala11Thr missense_variant 2/16 ENST00000323851.13 NP_006087.2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
NDRG1ENST00000323851.13 linkuse as main transcriptc.31G>A p.Ala11Thr missense_variant 2/161 NM_006096.4 ENSP00000319977 P1Q92597-1

Frequencies

GnomAD3 genomes
AF:
0.00137
AC:
209
AN:
152140
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.000386
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00419
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:
0.00185
Gnomad OTH
AF:
0.00143
GnomAD3 exomes
AF:
0.00117
AC:
294
AN:
251476
Hom.:
1
AF XY:
0.000979
AC XY:
133
AN XY:
135910
show subpopulations
Gnomad AFR exome
AF:
0.000308
Gnomad AMR exome
AF:
0.00228
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000327
Gnomad FIN exome
AF:
0.000139
Gnomad NFE exome
AF:
0.00171
Gnomad OTH exome
AF:
0.00195
GnomAD4 exome
AF:
0.00191
AC:
2797
AN:
1461886
Hom.:
4
Cov.:
32
AF XY:
0.00180
AC XY:
1307
AN XY:
727246
show subpopulations
Gnomad4 AFR exome
AF:
0.000508
Gnomad4 AMR exome
AF:
0.00239
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000116
Gnomad4 FIN exome
AF:
0.0000562
Gnomad4 NFE exome
AF:
0.00233
Gnomad4 OTH exome
AF:
0.00134
GnomAD4 genome
AF:
0.00137
AC:
209
AN:
152258
Hom.:
0
Cov.:
33
AF XY:
0.00130
AC XY:
97
AN XY:
74438
show subpopulations
Gnomad4 AFR
AF:
0.000385
Gnomad4 AMR
AF:
0.00418
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00185
Gnomad4 OTH
AF:
0.00142
Alfa
AF:
0.00144
Hom.:
0
Bravo
AF:
0.00175
TwinsUK
AF:
0.00324
AC:
12
ALSPAC
AF:
0.00311
AC:
12
ESP6500AA
AF:
0.000681
AC:
3
ESP6500EA
AF:
0.00174
AC:
15
ExAC
AF:
0.00102
AC:
124
EpiCase
AF:
0.00174
EpiControl
AF:
0.00184

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:6Benign:7
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Uncertain:2Benign:4
Uncertain significance, criteria provided, single submitterclinical testingMayo Clinic Laboratories, Mayo ClinicNov 25, 2022BP4 -
Likely benign, no assertion criteria providedclinical testingClinical Genetics, Academic Medical Center-- -
Likely benign, no assertion criteria providedclinical testingGenome Diagnostics Laboratory, University Medical Center Utrecht-- -
Uncertain significance, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenNov 01, 2020- -
Likely benign, criteria provided, single submitterclinical testingAthena DiagnosticsNov 22, 2019- -
Likely benign, criteria provided, single submitterclinical testingGeneDxMar 23, 2021This variant is associated with the following publications: (PMID: 32376792) -
Charcot-Marie-Tooth disease type 4D Uncertain:2
Uncertain significance, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 12, 2018This 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
Uncertain significance, criteria provided, single submitterclinical testingARUP Laboratories, Molecular Genetics and Genomics, ARUP LaboratoriesSep 22, 2023The NDRG1 c.31G>A; p.Ala11Thr variant (rs145871479) is reported in the literature in a cohort of CMT patients (Volodarsky 2021), and is also reported in ClinVar (Variation ID: 220934). This variant is observed in the general population with an overall allele frequency of 0.1% (313/282870 alleles, including 1 homozygote) in the Genome Aggregation Database. The alanine at codon 11 is weakly conserved, but computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.153). Due to limited information, the clinical significance of this variant is uncertain at this time. References: Volodarsky M et al. Comprehensive genetic sequence and copy number analysis for Charcot-Marie-Tooth disease in a Canadian cohort of 2517 patients. J Med Genet. 2021 Apr;58(4):284-288. PMID: 32376792. -
Charcot-Marie-Tooth disease type 4 Benign:2
Likely benign, no assertion criteria providedclinical testingNatera, Inc.Dec 27, 2019- -
Likely benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 29, 2024- -
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsDec 20, 2023The c.31G>A (p.A11T) alteration is located in exon 2 (coding exon 1) of the NDRG1 gene. This alteration results from a G to A substitution at nucleotide position 31, causing the alanine (A) at amino acid position 11 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -
NDRG1-related disorder Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact SciencesApr 21, 2023The NDRG1 c.31G>A variant is predicted to result in the amino acid substitution p.Ala11Thr. This variant was reported in an individual with Charcot-Marie-Tooth disease (Table S2, Volodarsky et al 2021. PubMed ID: 32376792). This variant is reported in 0.23% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/8-134296524-C-T). Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -
Charcot-Marie-Tooth disease Benign:1
Likely benign, criteria provided, single submitterclinical testingMolecular Genetics Laboratory, London Health Sciences Centre-- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.083
BayesDel_addAF
Benign
-0.32
T
BayesDel_noAF
Benign
-0.24
CADD
Benign
20
DANN
Benign
0.84
DEOGEN2
Benign
0.12
T;T;T;T;.;T;.;.;T;.;T
Eigen
Benign
-0.10
Eigen_PC
Benign
-0.0051
FATHMM_MKL
Benign
0.73
D
LIST_S2
Uncertain
0.88
.;D;T;T;D;D;.;D;D;D;D
M_CAP
Benign
0.0093
T
MetaRNN
Benign
0.0099
T;T;T;T;T;T;T;T;T;T;T
MetaSVM
Benign
-1.1
T
MutationAssessor
Benign
0.53
N;N;.;.;.;.;.;.;.;.;.
MutationTaster
Benign
1.0
D;D;N;N;N;N;N
PrimateAI
Uncertain
0.56
T
PROVEAN
Benign
1.7
N;N;N;N;N;N;N;N;N;N;N
REVEL
Benign
0.15
Sift
Benign
1.0
T;T;D;T;T;T;T;T;T;T;T
Sift4G
Benign
1.0
T;T;D;T;.;T;T;T;.;.;T
Polyphen
0.027
B;B;D;.;.;.;.;.;.;.;.
Vest4
0.47
MVP
0.44
MPC
0.29
ClinPred
0.042
T
GERP RS
5.0
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.11
gMVP
0.39

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs145871479; hg19: chr8-134296524; API