8-133237584-A-G

Variant names:

• chr8-133237584-A-G
• rs144034977
• NM_006096.4:c.*1294T>C

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_006096.4(NDRG1):​c.*1294T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00575 in 233,184 control chromosomes in the GnomAD database, including 18 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0078 (13 hom., cov: 32)
  • Exomes 𝑓: 0.0020 (5 hom.)
• Consequence: NDRG1 NM_006096.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.404
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• Charcot-Marie-Tooth disease type 4D

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), Illumina

ENSG00000289316 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 8-133237584-A-G is Benign according to our data. Variant chr8-133237584-A-G is described in ClinVar as [Benign]. Clinvar id is 362012.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00777 (1183/152330) while in subpopulation AFR AF = 0.0266 (1105/41566). AF 95% confidence interval is 0.0253. There are 13 homozygotes in GnomAd4. There are 558 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 13 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NDRG1	NM_006096.4	c.*1294T>C		3_prime_UTR_variant	Exon 16 of 16	ENST00000323851.13	NP_006087.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NDRG1	ENST00000323851.13	c.*1294T>C		3_prime_UTR_variant	Exon 16 of 16	1	NM_006096.4	ENSP00000319977.8

Frequencies

GnomAD3 genomes AF: 0.00776 AC: 1181 AN: 152212 Hom.: 13 Cov.: 32

Gnomad AFR AF: 0.0266

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00366

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00813

GnomAD4 exome AF: 0.00195 AC: 158 AN: 80854 Hom.: 5 Cov.: 0 AF XY: 0.00159 AC XY: 59 AN XY: 37174

African (AFR) AF: 0.0307 AC: 119 AN: 3882

American (AMR) AF: 0.00281 AC: 7 AN: 2488

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 5104

East Asian (EAS) AF: 0.00 AC: 0 AN: 11394

South Asian (SAS) AF: 0.00 AC: 0 AN: 702

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 64

Middle Eastern (MID) AF: 0.00204 AC: 1 AN: 490

European-Non Finnish (NFE) AF: 0.0000200 AC: 1 AN: 49970

Other (OTH) AF: 0.00444 AC: 30 AN: 6760

GnomAD4 genome AF: 0.00777 AC: 1183 AN: 152330 Hom.: 13 Cov.: 32 AF XY: 0.00749 AC XY: 558 AN XY: 74500

African (AFR) AF: 0.0266 AC: 1105 AN: 41566

American (AMR) AF: 0.00366 AC: 56 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5196

South Asian (SAS) AF: 0.000415 AC: 2 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68030

Other (OTH) AF: 0.00804 AC: 17 AN: 2114

Alfa AF: 0.000893 Hom.: 0

Bravo AF: 0.00884

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Charcot-Marie-Tooth disease type 4D Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	1.3
DANN	Benign	0.56
PhyloP100		-0.40
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs144034977; hg19: chr8-134249827;