20-36665299-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_032013.4(NDRG3):​c.695G>A​(p.Arg232His) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.000103 in 1,614,018 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000072 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00011 ( 0 hom. )

Consequence

NDRG3
NM_032013.4 missense, splice_region

Scores

8
5
6

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.08
Variant links:
Genes affected
NDRG3 (HGNC:14462): (NDRG family member 3) Predicted to be involved in signal transduction. Located in cytoplasm. [provided by Alliance of Genome Resources, Apr 2022]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.844

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
NDRG3NM_032013.4 linkc.695G>A p.Arg232His missense_variant, splice_region_variant Exon 11 of 16 ENST00000349004.6 NP_114402.1 Q9UGV2-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
NDRG3ENST00000349004.6 linkc.695G>A p.Arg232His missense_variant, splice_region_variant Exon 11 of 16 1 NM_032013.4 ENSP00000345292.1 Q9UGV2-1
NDRG3ENST00000359675.6 linkc.659G>A p.Arg220His missense_variant, splice_region_variant Exon 10 of 15 1 ENSP00000352703.2 Q9UGV2-2
NDRG3ENST00000373773.7 linkc.410G>A p.Arg137His missense_variant, splice_region_variant Exon 8 of 13 1 ENSP00000362878.3 F8WBF9
NDRG3ENST00000373803.6 linkc.695G>A p.Arg232His missense_variant, splice_region_variant Exon 11 of 17 5 ENSP00000362909.2 Q5TH30

Frequencies

GnomAD3 genomes
AF:
0.0000723
AC:
11
AN:
152136
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000241
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
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:
0.000147
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000239
AC:
6
AN:
251384
Hom.:
0
AF XY:
0.0000368
AC XY:
5
AN XY:
135870
show subpopulations
Gnomad AFR exome
AF:
0.0000615
Gnomad AMR exome
AF:
0.0000289
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000352
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.000106
AC:
155
AN:
1461764
Hom.:
0
Cov.:
31
AF XY:
0.000105
AC XY:
76
AN XY:
727196
show subpopulations
Gnomad4 AFR exome
AF:
0.0000597
Gnomad4 AMR exome
AF:
0.0000224
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.000134
Gnomad4 OTH exome
AF:
0.0000497
GnomAD4 genome
AF:
0.0000722
AC:
11
AN:
152254
Hom.:
0
Cov.:
32
AF XY:
0.0000537
AC XY:
4
AN XY:
74440
show subpopulations
Gnomad4 AFR
AF:
0.0000241
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000147
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000559
Hom.:
0
Bravo
AF:
0.0000567
TwinsUK
AF:
0.000270
AC:
1
ALSPAC
AF:
0.000259
AC:
1
ESP6500AA
AF:
0.000227
AC:
1
ESP6500EA
AF:
0.00
AC:
0
ExAC
AF:
0.0000330
AC:
4
EpiCase
AF:
0.000109
EpiControl
AF:
0.00

ClinVar

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

Submissions by phenotype

not specified Uncertain:1
Dec 02, 2024
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.695G>A (p.R232H) alteration is located in exon 11 (coding exon 10) of the NDRG3 gene. This alteration results from a G to A substitution at nucleotide position 695, causing the arginine (R) at amino acid position 232 to be replaced by a histidine (H). 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
0.86
BayesDel_addAF
Benign
-0.032
T
BayesDel_noAF
Benign
-0.20
CADD
Pathogenic
32
DANN
Pathogenic
1.0
DEOGEN2
Benign
0.12
T;.;T;T
Eigen
Pathogenic
0.76
Eigen_PC
Uncertain
0.65
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Uncertain
0.96
D;D;D;D
M_CAP
Uncertain
0.12
D
MetaRNN
Pathogenic
0.84
D;D;D;D
MetaSVM
Benign
-0.32
T
MutationAssessor
Pathogenic
3.1
.;.;M;.
PrimateAI
Benign
0.47
T
PROVEAN
Uncertain
-3.9
D;D;D;D
REVEL
Uncertain
0.57
Sift
Pathogenic
0.0
D;D;D;D
Sift4G
Pathogenic
0.0010
D;D;D;D
Polyphen
1.0
.;D;D;D
Vest4
0.88
MVP
0.62
MPC
1.0
ClinPred
0.98
D
GERP RS
3.9
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.85
gMVP
0.83

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.050
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: rs199601205; hg19: chr20-35293702; COSMIC: COSV62420946; COSMIC: COSV62420946; API