8-133259226-T-G

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_006096.4(NDRG1):​c.331A>C​(p.Met111Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0014 in 1,614,150 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). 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: 𝑓 0.0019 (2 hom., cov: 33)
  • Exomes 𝑓: 0.0013 (3 hom.)
• Consequence: NDRG1 NM_006096.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:6
• Conservation: PhyloP100: 0.412
• Publications: 6 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: Illumina, Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.010466516).
• BP6: Variant 8-133259226-T-G is Benign according to our data. Variant chr8-133259226-T-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 188374.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00186 (283/152288) while in subpopulation NFE AF = 0.00193 (131/68020). AF 95% confidence interval is 0.00166. There are 2 homozygotes in GnomAd4. There are 171 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006096.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NDRG1	NM_006096.4	MANE Select	c.331A>C	p.Met111Leu	missense	Exon 6 of 16	NP_006087.2
	NDRG1	NM_001374844.1		c.331A>C	p.Met111Leu	missense	Exon 6 of 16	NP_001361773.1
	NDRG1	NM_001135242.2		c.331A>C	p.Met111Leu	missense	Exon 6 of 16	NP_001128714.1	Q92597-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NDRG1	ENST00000323851.13	TSL:1 MANE Select	c.331A>C	p.Met111Leu	missense	Exon 6 of 16	ENSP00000319977.8	Q92597-1
	NDRG1	ENST00000522476.5	TSL:1	c.133A>C	p.Met45Leu	missense	Exon 4 of 14	ENSP00000427894.1	Q92597-2
	NDRG1	ENST00000414097.6	TSL:2	c.331A>C	p.Met111Leu	missense	Exon 6 of 16	ENSP00000404854.2	Q92597-1

Frequencies

GnomAD3 genomes AF: 0.00186 AC: 283 AN: 152170 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000393

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0133

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00193

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.00166 AC: 417 AN: 251480 AF XY: 0.00180

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.000260

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0106

Gnomad NFE exome AF: 0.00148

Gnomad OTH exome AF: 0.00147

GnomAD4 exome AF: 0.00135 AC: 1969 AN: 1461862 Hom.: 3 Cov.: 31 AF XY: 0.00139 AC XY: 1009 AN XY: 727228

African (AFR) AF: 0.000149 AC: 5 AN: 33480

American (AMR) AF: 0.000246 AC: 11 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00985 AC: 526 AN: 53412

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.00122 AC: 1358 AN: 1111988

Other (OTH) AF: 0.00111 AC: 67 AN: 60396

GnomAD4 genome AF: 0.00186 AC: 283 AN: 152288 Hom.: 2 Cov.: 33 AF XY: 0.00230 AC XY: 171 AN XY: 74464

African (AFR) AF: 0.0000962 AC: 4 AN: 41576

American (AMR) AF: 0.000392 AC: 6 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.00 AC: 0 AN: 4818

European-Finnish (FIN) AF: 0.0133 AC: 141 AN: 10614

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

European-Non Finnish (NFE) AF: 0.00193 AC: 131 AN: 68020

Other (OTH) AF: 0.000473 AC: 1 AN: 2116

Alfa AF: 0.00108 Hom.: 0

Bravo AF: 0.000623

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00234 AC: 9

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000930 AC: 8

ExAC AF: 0.00140 AC: 170

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000927

EpiControl AF: 0.000948

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	Charcot-Marie-Tooth disease type 4D (2)
-	-	2	not provided (2)
-	-	1	Charcot-Marie-Tooth disease (1)
-	-	1	Charcot-Marie-Tooth disease type 4 (1)
-	-	1	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	16
DANN	Benign	0.91
DEOGEN2	Benign	0.13	T
Eigen	Benign	-0.50
Eigen_PC	Benign	-0.34
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Benign	0.72	T
MetaRNN	Benign	0.010	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.76	N
PhyloP100		0.41
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.11
Sift	Benign	0.24	T
Sift4G	Benign	0.27	T
Polyphen		0.012	B
Vest4		0.17
MutPred		0.15		Loss of phosphorylation at Y110 (P = 0.0993)
MVP		0.21
MPC		0.28
ClinPred		0.017	T
GERP RS		1.7
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;