8-133238187-C-T

Variant names:

• chr8-133238187-C-T
• rs1049694
• NM_006096.4:c.*691G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong 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, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.716
• Publications: 7 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

ACMG classification

Our verdict: Benign. The variant received -20 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_multiple_submitters_no_conflicts, 2 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 rank	MANE	Protein	UniProt
NDRG1	NM_006096.4	c.*691G>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.*691G>A		3_prime_UTR_variant	Exon 16 of 16	1	NM_006096.4	ENSP00000319977.8

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

African (AFR) AF: 0.304 AC: 1175 AN: 3870

American (AMR) AF: 0.350 AC: 865 AN: 2474

Ashkenazi Jewish (ASJ) AF: 0.398 AC: 2020 AN: 5072

East Asian (EAS) AF: 0.0703 AC: 799 AN: 11364

South Asian (SAS) AF: 0.246 AC: 173 AN: 702

European-Finnish (FIN) AF: 0.362 AC: 21 AN: 58

Middle Eastern (MID) AF: 0.335 AC: 164 AN: 490

European-Non Finnish (NFE) AF: 0.345 AC: 17145 AN: 49728

Other (OTH) AF: 0.325 AC: 2185 AN: 6730

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

African (AFR) AF: 0.306 AC: 12662 AN: 41444

American (AMR) AF: 0.360 AC: 5499 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.382 AC: 1326 AN: 3470

East Asian (EAS) AF: 0.0541 AC: 280 AN: 5176

South Asian (SAS) AF: 0.249 AC: 1202 AN: 4820

European-Finnish (FIN) AF: 0.302 AC: 3188 AN: 10570

Middle Eastern (MID) AF: 0.313 AC: 92 AN: 294

European-Non Finnish (NFE) AF: 0.345 AC: 23415 AN: 67958

Other (OTH) AF: 0.326 AC: 690 AN: 2114

Alfa AF: 0.337 Hom.: 4240

Bravo AF: 0.327

Asia WGS AF: 0.161 AC: 565 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

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	-0.88
CADD	Benign	0.25
DANN	Benign	0.52
PhyloP100		-0.72
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
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: rs1049694; hg19: chr8-134250430;