8-133238187-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_006096.4(NDRG1):c.*691G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.316 in 232,512 control chromosomes in the GnomAD database, including 12,228 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.32 (8123 hom., cov: 32)
  • Exomes 𝑓: 0.30 (4105 hom.)
• Consequence: NDRG1 NM_006096.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.716

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=-0.88).
• BP6: Variant 8-133238187-C-T is Benign according to our data. Variant chr8-133238187-C-T is described in ClinVar as [Benign]. Clinvar id is 362019.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.352 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NDRG1	NM_006096.4	c.*691G>A		3_prime_UTR_variant	16/16	ENST00000323851.13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NDRG1	ENST00000323851.13	c.*691G>A		3_prime_UTR_variant	16/16	1	NM_006096.4	P1

Frequencies

GnomAD3 genomes AF: 0.321 AC: 48777 AN: 151906 Hom.: 8115 Cov.: 32

Gnomad AFR AF: 0.305

Gnomad AMI AF: 0.513

Gnomad AMR AF: 0.360

Gnomad ASJ AF: 0.382

Gnomad EAS AF: 0.0545

Gnomad SAS AF: 0.248

Gnomad FIN AF: 0.302

Gnomad MID AF: 0.326

Gnomad NFE AF: 0.344

Gnomad OTH AF: 0.328

GnomAD4 exome AF: 0.305 AC: 24547 AN: 80488 Hom.: 4105 Cov.: 0 AF XY: 0.308 AC XY: 11383 AN XY: 37000

Gnomad4 AFR exome AF: 0.304

Gnomad4 AMR exome AF: 0.350

Gnomad4 ASJ exome AF: 0.398

Gnomad4 EAS exome AF: 0.0703

Gnomad4 SAS exome AF: 0.246

Gnomad4 FIN exome AF: 0.362

Gnomad4 NFE exome AF: 0.345

Gnomad4 OTH exome AF: 0.325

GnomAD4 genome AF: 0.321 AC: 48822 AN: 152024 Hom.: 8123 Cov.: 32 AF XY: 0.318 AC XY: 23596 AN XY: 74312

Gnomad4 AFR AF: 0.306

Gnomad4 AMR AF: 0.360

Gnomad4 ASJ AF: 0.382

Gnomad4 EAS AF: 0.0541

Gnomad4 SAS AF: 0.249

Gnomad4 FIN AF: 0.302

Gnomad4 NFE AF: 0.345

Gnomad4 OTH AF: 0.326

Alfa AF: 0.337 Hom.: 3594

Bravo AF: 0.327

Asia WGS AF: 0.161 AC: 565 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

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	-0.88
Cadd	Benign	0.25
Dann	Benign	0.52
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: rs1049694; hg19: chr8-134250430;