rs2233319

chr8-133264553-T-C

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 8P and 16B. PVS1 BP6_Very_Strong BS1 BS2

The ENST00000522476.5(NDRG1):c.1A>G(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00163 in 1,614,166 control chromosomes in the GnomAD database, including 26 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0078 (13 hom., cov: 33)
  • Exomes 𝑓: 0.00099 (13 hom.)
• Consequence: NDRG1 ENST00000522476.5 start_lost
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 3.24

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]

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• PVS1: Start lost variant, no new inframe start found.
• BP6: Variant 8-133264553-T-C is Benign according to our data. Variant chr8-133264553-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 362040.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-133264553-T-C is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00775 (1181/152356) while in subpopulation AFR AF= 0.0251 (1045/41576). AF 95% confidence interval is 0.0239. There are 13 homozygotes in gnomad4. There are 563 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 13 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NDRG1	NM_006096.4	c.199A>G	p.Met67Val	missense_variant	4/16	ENST00000323851.13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NDRG1	ENST00000323851.13	c.199A>G	p.Met67Val	missense_variant	4/16	1	NM_006096.4	P1

Frequencies

GnomAD3 genomes AF: 0.00774 AC: 1179 AN: 152238 Hom.: 13 Cov.: 33

Gnomad AFR AF: 0.0252

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00399

Gnomad ASJ AF: 0.0127

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000162

Gnomad OTH AF: 0.00907

GnomAD3 exomes AF: 0.00239 AC: 601 AN: 251482 Hom.: 5 AF XY: 0.00184 AC XY: 250 AN XY: 135916

Gnomad AFR exome AF: 0.0263

Gnomad AMR exome AF: 0.00165

Gnomad ASJ exome AF: 0.00823

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000220

Gnomad OTH exome AF: 0.00114

GnomAD4 exome AF: 0.000993 AC: 1451 AN: 1461810 Hom.: 13 Cov.: 30 AF XY: 0.000919 AC XY: 668 AN XY: 727226

Gnomad4 AFR exome AF: 0.0259

Gnomad4 AMR exome AF: 0.00157

Gnomad4 ASJ exome AF: 0.00934

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000890

Gnomad4 OTH exome AF: 0.00250

GnomAD4 genome AF: 0.00775 AC: 1181 AN: 152356 Hom.: 13 Cov.: 33 AF XY: 0.00756 AC XY: 563 AN XY: 74504

Gnomad4 AFR AF: 0.0251

Gnomad4 AMR AF: 0.00399

Gnomad4 ASJ AF: 0.0127

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000162

Gnomad4 OTH AF: 0.00898

Alfa AF: 0.00189 Hom.: 3

Bravo AF: 0.00890

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.0252 AC: 111

ESP6500EA AF: 0.000814 AC: 7

ExAC AF: 0.00281 AC: 341

Asia WGS AF: 0.00144 AC: 6 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.000296

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Charcot-Marie-Tooth disease type 4D Benign:2

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 07, 2019	- -
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. -

Charcot-Marie-Tooth disease Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Molecular Genetics Laboratory, London Health Sciences Centre

-

- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

Sep 15, 2020

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 03, 2015

- -

Charcot-Marie-Tooth disease type 4 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 30, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.31
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.40
Cadd	Benign	23
Dann	Uncertain	0.98
DEOGEN2	Benign	0.15	T;T;.;.;.;T;.;.;T;.;T;.
Eigen	Benign	-0.26
Eigen_PC	Benign	-0.10
FATHMM_MKL	Uncertain	0.79	D
MetaRNN	Benign	0.0081	T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.69	N;N;.;.;.;.;.;.;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-1.1	N;N;N;N;N;N;N;N;N;N;N;N
REVEL	Benign	0.11
Sift	Uncertain	0.0010	D;D;D;D;D;D;D;D;D;D;D;T
Sift4G	Uncertain	0.010	D;D;D;.;D;D;D;D;.;.;D;.
Polyphen		0.014	B;B;.;.;.;.;.;.;.;.;.;.
Vest4		0.43
MVP		0.19
MPC		0.38
ClinPred		0.080	T
GERP RS		3.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.49
gMVP		0.60

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

Other links and lift over

dbSNP: rs2233319; hg19: chr8-134276796;