chr8-133238012-T-A

Position:

• chr8-133238012-T-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_006096.4(NDRG1):​c.*866A>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0233 in 233,114 control chromosomes in the GnomAD database, including 113 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.028 (95 hom., cov: 32)
  • Exomes 𝑓: 0.015 (18 hom.)
• Consequence: NDRG1 NM_006096.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.373

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 8-133238012-T-A is Benign according to our data. Variant chr8-133238012-T-A is described in ClinVar as [Benign]. Clinvar id is 362016.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0276 (4195/152250) while in subpopulation AFR AF= 0.0497 (2062/41526). AF 95% confidence interval is 0.0479. There are 95 homozygotes in gnomad4. There are 2179 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 95 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NDRG1	NM_006096.4	c.*866A>T		3_prime_UTR_variant	16/16	ENST00000323851.13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NDRG1	ENST00000323851.13	c.*866A>T		3_prime_UTR_variant	16/16	1	NM_006096.4	P1

Frequencies

GnomAD3 genomes AF: 0.0276 AC: 4193 AN: 152132 Hom.: 95 Cov.: 32

Gnomad AFR AF: 0.0497

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0262

Gnomad ASJ AF: 0.0222

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0180

Gnomad FIN AF: 0.0487

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.0147

Gnomad OTH AF: 0.0235

GnomAD4 exome AF: 0.0152 AC: 1233 AN: 80864 Hom.: 18 Cov.: 0 AF XY: 0.0150 AC XY: 557 AN XY: 37180

Gnomad4 AFR exome AF: 0.0548

Gnomad4 AMR exome AF: 0.0309

Gnomad4 ASJ exome AF: 0.0264

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0229

Gnomad4 FIN exome AF: 0.0500

Gnomad4 NFE exome AF: 0.0130

Gnomad4 OTH exome AF: 0.0194

GnomAD4 genome AF: 0.0276 AC: 4195 AN: 152250 Hom.: 95 Cov.: 32 AF XY: 0.0293 AC XY: 2179 AN XY: 74470

Gnomad4 AFR AF: 0.0497

Gnomad4 AMR AF: 0.0261

Gnomad4 ASJ AF: 0.0222

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0182

Gnomad4 FIN AF: 0.0487

Gnomad4 NFE AF: 0.0147

Gnomad4 OTH AF: 0.0232

Alfa AF: 0.0108 Hom.: 7

Bravo AF: 0.0266

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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	-0.80
CADD	Benign	3.8
DANN	Benign	0.76
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

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: rs16904865; hg19: chr8-134250255;