rs765621411

Positions:

chr8-133239012-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PVS1_StrongPM2

The NM_006096.4(NDRG1):c.1051C>T(p.Arg351*) variant causes a stop gained change. The variant allele was found at a frequency of 0.0000463 in 1,598,292 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000079 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000043 ( 1 hom. )

Consequence

NDRG1
NM_006096.4 stop_gained

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 3.59

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 links:

NDRG1 (HGNC:):

NDRG1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PVS1

Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.113 CDS is truncated, and there are 0 pathogenic variants in the truncated region.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NDRG1	NM_006096.4 linkuse as main transcript	c.1051C>T	p.Arg351*	stop_gained	16/16	ENST00000323851.13	NP_006087.2	Q92597-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NDRG1	ENST00000323851.13 linkuse as main transcript	c.1051C>T	p.Arg351*	stop_gained	16/16	1	NM_006096.4	ENSP00000319977.8		Q92597-1

Frequencies

GnomAD3 genomes

AF:

0.0000789

AC:

AN:

152058

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.000848

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000918

AC:

AN:

217764

Hom.:

AF XY:

0.000110

AC XY:

AN XY:

117910

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000787

Gnomad NFE exome

AF:

0.0000615

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000429

AC:

AN:

1446234

Hom.:

Cov.:

AF XY:

0.0000432

AC XY:

AN XY:

717754

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000480

Gnomad4 FIN exome

AF:

0.000431

Gnomad4 NFE exome

AF:

0.0000316

Gnomad4 OTH exome

AF:

0.0000167

GnomAD4 genome

AF:

0.0000789

AC:

AN:

152058

Hom.:

Cov.:

AF XY:

0.000148

AC XY:

AN XY:

74270

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.000848

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000756

ExAC

AF:

0.0000924

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Charcot-Marie-Tooth disease type 4

Uncertain:2

Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jul 26, 2022	This sequence change creates a premature translational stop signal (p.Arg351*) in the NDRG1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 44 amino acid(s) of the NDRG1 protein. This variant is present in population databases (rs765621411, gnomAD 0.07%), including at least one homozygous and/or hemizygous individual. This variant has not been reported in the literature in individuals affected with NDRG1-related conditions. ClinVar contains an entry for this variant (Variation ID: 240289). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Jul 14, 2022

Variant summary: NDRG1 c.1051C>T (p.Arg351X) results in a premature termination codon in the last exon of the gene, therefore it is not expected to cause nonsense mediated decay (NMD), but is predicted to cause a truncation of the encoded protein, removing amino acids 351 to 394 (InterPro). No truncations downstream of this position have been reported in affected individuals (HGMD). The variant allele was found at a frequency of 9.2e-05 in 217764 control chromosomes in the gnomAD database, including 1 homozygote. To our knowledge, no occurrence of c.1051C>T in individuals affected with Charcot-Marie Disease Type 4D and no experimental evidence demonstrating its impact on protein function have been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014, and both of them classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.45

BayesDel_noAF

Pathogenic

0.50

CADD

Pathogenic

DANN

Uncertain

1.0

Eigen

Pathogenic

0.72

Eigen_PC

Uncertain

0.58

FATHMM_MKL

Uncertain

0.94

Vest4

0.85

GERP RS

4.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

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

LitVar

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

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over