8-133237922-A-G

Variant names:

• chr8-133237922-A-G
• rs1049697
• NM_006096.4:c.*956T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_006096.4(NDRG1):​c.*956T>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 0.83 in 232,876 control chromosomes in the GnomAD database, including 80,814 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.84 (53380 hom., cov: 30)
  • Exomes 𝑓: 0.82 (27434 hom.)
• Consequence: NDRG1 NM_006096.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.670
• Publications: 10 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 8-133237922-A-G is Benign according to our data. Variant chr8-133237922-A-G is described in ClinVar as [Benign]. Clinvar id is 362015.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.906 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NDRG1	NM_006096.4	c.*956T>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.*956T>C		3_prime_UTR_variant	Exon 16 of 16	1	NM_006096.4	ENSP00000319977.8

Frequencies

GnomAD3 genomes AF: 0.835 AC: 126832 AN: 151886 Hom.: 53332 Cov.: 30

Gnomad AFR AF: 0.914

Gnomad AMI AF: 0.928

Gnomad AMR AF: 0.809

Gnomad ASJ AF: 0.906

Gnomad EAS AF: 0.700

Gnomad SAS AF: 0.791

Gnomad FIN AF: 0.701

Gnomad MID AF: 0.896

Gnomad NFE AF: 0.822

Gnomad OTH AF: 0.849

GnomAD4 exome AF: 0.821 AC: 66432 AN: 80870 Hom.: 27434 Cov.: 0 AF XY: 0.823 AC XY: 30589 AN XY: 37172

African (AFR) AF: 0.916 AC: 3559 AN: 3884

American (AMR) AF: 0.778 AC: 1939 AN: 2492

Ashkenazi Jewish (ASJ) AF: 0.896 AC: 4588 AN: 5122

East Asian (EAS) AF: 0.723 AC: 8247 AN: 11402

South Asian (SAS) AF: 0.765 AC: 537 AN: 702

European-Finnish (FIN) AF: 0.758 AC: 47 AN: 62

Middle Eastern (MID) AF: 0.878 AC: 432 AN: 492

European-Non Finnish (NFE) AF: 0.829 AC: 41419 AN: 49956

Other (OTH) AF: 0.838 AC: 5664 AN: 6758

GnomAD4 genome AF: 0.835 AC: 126938 AN: 152006 Hom.: 53380 Cov.: 30 AF XY: 0.827 AC XY: 61427 AN XY: 74294

African (AFR) AF: 0.914 AC: 37899 AN: 41478

American (AMR) AF: 0.808 AC: 12340 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.906 AC: 3144 AN: 3470

East Asian (EAS) AF: 0.700 AC: 3598 AN: 5138

South Asian (SAS) AF: 0.790 AC: 3809 AN: 4822

European-Finnish (FIN) AF: 0.701 AC: 7392 AN: 10538

Middle Eastern (MID) AF: 0.891 AC: 262 AN: 294

European-Non Finnish (NFE) AF: 0.822 AC: 55858 AN: 67982

Other (OTH) AF: 0.849 AC: 1790 AN: 2108

Alfa AF: 0.830 Hom.: 51387

Bravo AF: 0.848

Asia WGS AF: 0.750 AC: 2610 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

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

Jan 13, 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	-0.86
CADD	Benign	0.14
DANN	Benign	0.65
PhyloP100		-0.67
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.3
Mutation Taster		=100/0	polymorphism (auto)

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: rs1049697; hg19: chr8-134250165;