rs2233328

Variant names:

• chr8-133259226-T-A
• rs2233328
• NM_006096.4:c.331A>T

Your query was ambiguous. Multiple possible variants found:

• chr8-133259226-T-A
• chr8-133259226-T-C
• chr8-133259226-T-G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_006096.4(NDRG1):​c.331A>T​(p.Met111Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M111R) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: NDRG1 NM_006096.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.412
• 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.17069438).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NDRG1	NM_006096.4	c.331A>T	p.Met111Leu	missense_variant	Exon 6 of 16	ENST00000323851.13	NP_006087.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NDRG1	ENST00000323851.13	c.331A>T	p.Met111Leu	missense_variant	Exon 6 of 16	1	NM_006096.4	ENSP00000319977.8

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	16
DANN	Benign	0.92
DEOGEN2	Benign	0.13	T;.;T;.;.;.;T;.;.;T;.;T
Eigen	Benign	-0.50
Eigen_PC	Benign	-0.34
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.72	.;T;T;T;T;T;T;.;T;T;T;T
M_CAP	Benign	0.0069	T
MetaRNN	Benign	0.17	T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.76	N;.;N;.;.;.;.;.;.;.;.;.
PhyloP100		0.41
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-1.4	N;N;N;N;N;N;N;N;N;N;N;N
REVEL	Benign	0.11
Sift	Benign	0.24	T;T;T;T;T;T;T;T;T;T;T;T
Sift4G	Benign	0.27	T;T;T;T;.;T;T;T;T;.;.;T
Polyphen		0.012	B;.;B;.;.;.;.;.;.;.;.;.
Vest4		0.17
MutPred		0.15		Loss of phosphorylation at Y110 (P = 0.0993);.;Loss of phosphorylation at Y110 (P = 0.0993);.;.;.;Loss of phosphorylation at Y110 (P = 0.0993);Loss of phosphorylation at Y110 (P = 0.0993);Loss of phosphorylation at Y110 (P = 0.0993);.;Loss of phosphorylation at Y110 (P = 0.0993);.;
MVP		0.21
MPC		0.28
ClinPred		0.34	T
GERP RS		1.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.9
Varity_R		0.19
gMVP		0.48
Mutation Taster		=99/1	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: rs2233328; hg19: chr8-134271469;