8-133238225-A-G

Variant names:

• chr8-133238225-A-G
• rs147301529
• NM_006096.4:c.*653T>C

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_006096.4(NDRG1):​c.*653T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00927 in 232,788 control chromosomes in the GnomAD database, including 57 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.013 (55 hom., cov: 33)
  • Exomes 𝑓: 0.0024 (2 hom.)
• Consequence: NDRG1 NM_006096.4 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.974
• 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

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 8-133238225-A-G is Benign according to our data. Variant chr8-133238225-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 362021.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0129 (1965/152336) while in subpopulation AFR AF = 0.0454 (1886/41566). AF 95% confidence interval is 0.0437. There are 55 homozygotes in GnomAd4. There are 936 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 55 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NDRG1	NM_006096.4	c.*653T>C		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.*653T>C		3_prime_UTR_variant	Exon 16 of 16	1	NM_006096.4	ENSP00000319977.8

Frequencies

GnomAD3 genomes AF: 0.0128 AC: 1949 AN: 152218 Hom.: 55 Cov.: 33

Gnomad AFR AF: 0.0451

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00321

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000220

Gnomad OTH AF: 0.00716

GnomAD4 exome AF: 0.00239 AC: 192 AN: 80452 Hom.: 2 Cov.: 0 AF XY: 0.00192 AC XY: 71 AN XY: 36978

African (AFR) AF: 0.0376 AC: 145 AN: 3860

American (AMR) AF: 0.00323 AC: 8 AN: 2478

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 5086

East Asian (EAS) AF: 0.00 AC: 0 AN: 11348

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 60

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 486

European-Non Finnish (NFE) AF: 0.000181 AC: 9 AN: 49700

Other (OTH) AF: 0.00446 AC: 30 AN: 6730

GnomAD4 genome AF: 0.0129 AC: 1965 AN: 152336 Hom.: 55 Cov.: 33 AF XY: 0.0126 AC XY: 936 AN XY: 74508

African (AFR) AF: 0.0454 AC: 1886 AN: 41566

American (AMR) AF: 0.00320 AC: 49 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000220 AC: 15 AN: 68034

Other (OTH) AF: 0.00709 AC: 15 AN: 2116

Alfa AF: 0.00793 Hom.: 5

Bravo AF: 0.0145

Asia WGS AF: 0.00404 AC: 14 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	4.4
DANN	Benign	0.49
PhyloP100		0.97
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: rs147301529; hg19: chr8-134250468;