chr8-133238012-T-A

Variant names:

• chr8-133238012-T-A
• rs16904865
• NM_006096.4:c.*866A>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• 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
• Publications: 1 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 95 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NDRG1	NM_006096.4	c.*866A>T		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.*866A>T		3_prime_UTR_variant	Exon 16 of 16	1	NM_006096.4	ENSP00000319977.8

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

African (AFR) AF: 0.0548 AC: 213 AN: 3886

American (AMR) AF: 0.0309 AC: 77 AN: 2494

Ashkenazi Jewish (ASJ) AF: 0.0264 AC: 135 AN: 5116

East Asian (EAS) AF: 0.00 AC: 0 AN: 11398

South Asian (SAS) AF: 0.0229 AC: 16 AN: 700

European-Finnish (FIN) AF: 0.0500 AC: 3 AN: 60

Middle Eastern (MID) AF: 0.0122 AC: 6 AN: 490

European-Non Finnish (NFE) AF: 0.0130 AC: 652 AN: 49966

Other (OTH) AF: 0.0194 AC: 131 AN: 6754

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

African (AFR) AF: 0.0497 AC: 2062 AN: 41526

American (AMR) AF: 0.0261 AC: 400 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0222 AC: 77 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.0182 AC: 88 AN: 4826

European-Finnish (FIN) AF: 0.0487 AC: 517 AN: 10606

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.0147 AC: 997 AN: 68018

Other (OTH) AF: 0.0232 AC: 49 AN: 2110

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

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	3.8
DANN	Benign	0.76
PhyloP100		-0.37
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
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: rs16904865; hg19: chr8-134250255;