8-133237922-A-G

Position:

• chr8-133237922-A-G

Variant summary

Our verdict is Benign. Variant got -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

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -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/exons	MANE	Protein	UniProt
NDRG1	NM_006096.4	c.*956T>C		3_prime_UTR_variant	16/16	ENST00000323851.13	NP_006087.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NDRG1	ENST00000323851.13	c.*956T>C		3_prime_UTR_variant	16/16	1	NM_006096.4	ENSP00000319977	P1
	ENST00000688585.1	n.6T>C		non_coding_transcript_exon_variant	1/1

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

Gnomad4 AFR exome AF: 0.916

Gnomad4 AMR exome AF: 0.778

Gnomad4 ASJ exome AF: 0.896

Gnomad4 EAS exome AF: 0.723

Gnomad4 SAS exome AF: 0.765

Gnomad4 FIN exome AF: 0.758

Gnomad4 NFE exome AF: 0.829

Gnomad4 OTH exome AF: 0.838

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

Gnomad4 AFR AF: 0.914

Gnomad4 AMR AF: 0.808

Gnomad4 ASJ AF: 0.906

Gnomad4 EAS AF: 0.700

Gnomad4 SAS AF: 0.790

Gnomad4 FIN AF: 0.701

Gnomad4 NFE AF: 0.822

Gnomad4 OTH AF: 0.849

Alfa AF: 0.824 Hom.: 30433

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

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

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

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.14
DANN	Benign	0.65
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.3

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: rs1049697; hg19: chr8-134250165;