rs2272653

Variant summary

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

The NM_006096.4(NDRG1):c.64-6T>C 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 0.567 in 1,612,932 control chromosomes in the GnomAD database, including 265,351 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/2 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.64 ( 32790 hom., cov: 32)

Exomes 𝑓: 0.56 ( 232561 hom. )

Consequence

NDRG1
NM_006096.4 splice_region, splice_polypyrimidine_tract, intron

Scores

Splicing: ADA: 0.000008000

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: 0.573

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=-0.73).

BP6

Variant 8-133280273-A-G is Benign according to our data. Variant chr8-133280273-A-G is described in ClinVar as [Benign]. Clinvar id is 259916.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-133280273-A-G is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.855 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.64-6T>C		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.64-6T>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_006096.4	P1	Q92597-1

Frequencies

GnomAD3 genomes

AF:

0.640

AC:

97248

AN:

151950

Hom.:

32741

Cov.:

show subpopulations

Gnomad AFR

AF:

0.862

Gnomad AMI

AF:

0.499

Gnomad AMR

AF:

0.534

Gnomad ASJ

AF:

0.641

Gnomad EAS

AF:

0.463

Gnomad SAS

AF:

0.410

Gnomad FIN

AF:

0.579

Gnomad MID

AF:

0.649

Gnomad NFE

AF:

0.570

Gnomad OTH

AF:

0.648

GnomAD3 exomes

AF:

0.556

AC:

139553

AN:

251082

Hom.:

40290

AF XY:

0.549

AC XY:

74453

AN XY:

135720

show subpopulations

Gnomad AFR exome

AF:

0.870

Gnomad AMR exome

AF:

0.469

Gnomad ASJ exome

AF:

0.635

Gnomad EAS exome

AF:

0.465

Gnomad SAS exome

AF:

0.435

Gnomad FIN exome

AF:

0.577

Gnomad NFE exome

AF:

0.572

Gnomad OTH exome

AF:

0.577

GnomAD4 exome

AF:

0.560

AC:

817722

AN:

1460864

Hom.:

232561

Cov.:

AF XY:

0.555

AC XY:

403631

AN XY:

726762

show subpopulations

Gnomad4 AFR exome

AF:

0.879

Gnomad4 AMR exome

AF:

0.478

Gnomad4 ASJ exome

AF:

0.643

Gnomad4 EAS exome

AF:

0.468

Gnomad4 SAS exome

AF:

0.438

Gnomad4 FIN exome

AF:

0.580

Gnomad4 NFE exome

AF:

0.562

Gnomad4 OTH exome

AF:

0.582

GnomAD4 genome

AF:

0.640

AC:

97347

AN:

152068

Hom.:

32790

Cov.:

AF XY:

0.632

AC XY:

46944

AN XY:

74330

show subpopulations

Gnomad4 AFR

AF:

0.862

Gnomad4 AMR

AF:

0.534

Gnomad4 ASJ

AF:

0.641

Gnomad4 EAS

AF:

0.463

Gnomad4 SAS

AF:

0.409

Gnomad4 FIN

AF:

0.579

Gnomad4 NFE

AF:

0.570

Gnomad4 OTH

AF:

0.645

Alfa

AF:

0.598

Hom.:

23991

Bravo

AF:

0.653

Asia WGS

AF:

0.507

AC:

1765

AN:

3478

EpiCase

AF:

0.575

EpiControl

AF:

0.575

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jul 26, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 20, 2017	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

Charcot-Marie-Tooth disease type 4D

Benign:3

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, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
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	Invitae	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

clinical testing

GeneDx

Mar 03, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.73

Cadd

Benign

Dann

Benign

0.49

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.0000080

dbscSNV1_RF

Benign

0.0

SpliceAI score (max)

0.020

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