rs2227262

Positions:

chr8-133247931-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_006096.4(NDRG1):c.756-5C>T variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.147 in 1,613,166 control chromosomes in the GnomAD database, including 18,280 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.12 ( 1243 hom., cov: 33)

Exomes 𝑓: 0.15 ( 17037 hom. )

Consequence

NDRG1
NM_006096.4 splice_region, splice_polypyrimidine_tract, intron

Scores

Splicing: ADA: 0.00005743

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 1.84

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.83).

BP6

Variant 8-133247931-G-A is Benign according to our data. Variant chr8-133247931-G-A is described in ClinVar as [Benign]. Clinvar id is 138434.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-133247931-G-A is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.185 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NDRG1	NM_006096.4 linkuse as main transcript	c.756-5C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000323851.13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NDRG1	ENST00000323851.13 linkuse as main transcript	c.756-5C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_006096.4	P1	Q92597-1

Frequencies

GnomAD3 genomes

AF:

0.116

AC:

17582

AN:

152100

Hom.:

1243

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0309

Gnomad AMI

AF:

0.124

Gnomad AMR

AF:

0.112

Gnomad ASJ

AF:

0.160

Gnomad EAS

AF:

0.102

Gnomad SAS

AF:

0.196

Gnomad FIN

AF:

0.152

Gnomad MID

AF:

0.155

Gnomad NFE

AF:

0.155

Gnomad OTH

AF:

0.118

GnomAD3 exomes

AF:

0.139

AC:

35045

AN:

251486

Hom.:

2733

AF XY:

0.146

AC XY:

19829

AN XY:

135916

show subpopulations

Gnomad AFR exome

AF:

0.0263

Gnomad AMR exome

AF:

0.107

Gnomad ASJ exome

AF:

0.174

Gnomad EAS exome

AF:

0.100

Gnomad SAS exome

AF:

0.191

Gnomad FIN exome

AF:

0.151

Gnomad NFE exome

AF:

0.152

Gnomad OTH exome

AF:

0.141

GnomAD4 exome

AF:

0.150

AC:

218866

AN:

1460948

Hom.:

17037

Cov.:

AF XY:

0.152

AC XY:

110541

AN XY:

726792

show subpopulations

Gnomad4 AFR exome

AF:

0.0242

Gnomad4 AMR exome

AF:

0.108

Gnomad4 ASJ exome

AF:

0.171

Gnomad4 EAS exome

AF:

0.132

Gnomad4 SAS exome

AF:

0.188

Gnomad4 FIN exome

AF:

0.147

Gnomad4 NFE exome

AF:

0.153

Gnomad4 OTH exome

AF:

0.144

GnomAD4 genome

AF:

0.115

AC:

17565

AN:

152218

Hom.:

1243

Cov.:

AF XY:

0.116

AC XY:

8642

AN XY:

74408

show subpopulations

Gnomad4 AFR

AF:

0.0308

Gnomad4 AMR

AF:

0.111

Gnomad4 ASJ

AF:

0.160

Gnomad4 EAS

AF:

0.101

Gnomad4 SAS

AF:

0.195

Gnomad4 FIN

AF:

0.152

Gnomad4 NFE

AF:

0.155

Gnomad4 OTH

AF:

0.117

Alfa

AF:

0.146

Hom.:

2076

Bravo

AF:

0.106

Asia WGS

AF:

0.121

AC:

420

AN:

3478

EpiCase

AF:

0.156

EpiControl

AF:

0.151

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jul 12, 2017	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 15, 2014	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Charcot-Marie-Tooth disease type 4D

Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This 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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 10, 2021	- -

Charcot-Marie-Tooth disease type 4

Benign:2

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

Charcot-Marie-Tooth disease

Benign:1

Benign, criteria provided, single submitter

clinical testing

Molecular Genetics Laboratory, London Health Sciences Centre

- -

not provided

Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.83

CADD

Benign

9.6

DANN

Benign

0.71

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000057

dbscSNV1_RF

Benign

0.0020

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