chr8-133238044-A-T

Variant names:

• chr8-133238044-A-T
• rs79281324
• NM_006096.4:c.*834T>A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_006096.4(NDRG1):​c.*834T>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 0.0243 in 233,102 control chromosomes in the GnomAD database, including 313 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.033 (287 hom., cov: 32)
  • Exomes 𝑓: 0.0076 (26 hom.)
• Consequence: NDRG1 NM_006096.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.30
• Publications: 0 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 8-133238044-A-T is Benign according to our data. Variant chr8-133238044-A-T is described in ClinVar as [Benign]. Clinvar id is 362017.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.112 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NDRG1	NM_006096.4	c.*834T>A		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.*834T>A		3_prime_UTR_variant	Exon 16 of 16	1	NM_006096.4	ENSP00000319977.8

Frequencies

GnomAD3 genomes AF: 0.0330 AC: 5026 AN: 152140 Hom.: 285 Cov.: 32

Gnomad AFR AF: 0.114

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0129

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000768

Gnomad SAS AF: 0.00248

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000191

Gnomad OTH AF: 0.0292

GnomAD4 exome AF: 0.00757 AC: 612 AN: 80844 Hom.: 26 Cov.: 0 AF XY: 0.00627 AC XY: 233 AN XY: 37144

African (AFR) AF: 0.116 AC: 451 AN: 3890

American (AMR) AF: 0.0132 AC: 33 AN: 2494

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 5120

East Asian (EAS) AF: 0.0000878 AC: 1 AN: 11386

South Asian (SAS) AF: 0.00 AC: 0 AN: 704

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 66

Middle Eastern (MID) AF: 0.00410 AC: 2 AN: 488

European-Non Finnish (NFE) AF: 0.0000601 AC: 3 AN: 49938

Other (OTH) AF: 0.0181 AC: 122 AN: 6758

GnomAD4 genome AF: 0.0331 AC: 5042 AN: 152258 Hom.: 287 Cov.: 32 AF XY: 0.0315 AC XY: 2349 AN XY: 74462

African (AFR) AF: 0.115 AC: 4755 AN: 41520

American (AMR) AF: 0.0129 AC: 197 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.000578 AC: 3 AN: 5194

South Asian (SAS) AF: 0.00249 AC: 12 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000191 AC: 13 AN: 68010

Other (OTH) AF: 0.0289 AC: 61 AN: 2112

Alfa AF: 0.0249 Hom.: 14

Bravo AF: 0.0376

Asia WGS AF: 0.00779 AC: 27 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

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	-0.82
CADD	Benign	4.4
DANN	Benign	0.71
PhyloP100		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: rs79281324; hg19: chr8-134250287;