rs143549909

Variant names:

• chr8-133250478-G-T
• rs143549909
• NM_006096.4:c.660C>A
• NDRG1 p.Asn220Lys

Your query was ambiguous. Multiple possible variants found:

• chr8-133250478-G-T
• chr8-133250478-G-A

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_Moderate BP6 BS1

The NM_006096.4(NDRG1):​c.660C>A​(p.Asn220Lys) variant causes a missense change. The variant allele was found at a frequency of 0.0001 in 1,614,070 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00012 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000099 (1 hom.)
• Consequence: NDRG1 NM_006096.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4
• Conservation: PhyloP100: 5.90
• Publications: 1 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, Labcorp Genetics (formerly Invitae), Orphanet

ACMG classification

Our verdict: Benign. The variant received -7 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.17246279).
• BP6: Variant 8-133250478-G-T is Benign according to our data. Variant chr8-133250478-G-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 426529.
• BS1: Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.0000985 (144/1461892) while in subpopulation MID AF = 0.00156 (9/5768). AF 95% confidence interval is 0.000814. There are 1 homozygotes in GnomAdExome4. There are 75 alleles in the male GnomAdExome4 subpopulation. Median coverage is 31. This position passed quality control check.

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.660C>A	p.Asn220Lys	missense	Exon 10 of 16	NP_006087.2
	NDRG1	NM_001374844.1		c.711C>A	p.Asn237Lys	missense	Exon 10 of 16	NP_001361773.1
	NDRG1	NM_001135242.2		c.660C>A	p.Asn220Lys	missense	Exon 10 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.660C>A	p.Asn220Lys	missense	Exon 10 of 16	ENSP00000319977.8	Q92597-1
	NDRG1	ENST00000522476.5	TSL:1	c.462C>A	p.Asn154Lys	missense	Exon 8 of 14	ENSP00000427894.1	Q92597-2
	NDRG1	ENST00000414097.6	TSL:2	c.660C>A	p.Asn220Lys	missense	Exon 10 of 16	ENSP00000404854.2	Q92597-1

Frequencies

GnomAD3 genomes AF: 0.000118 AC: 18 AN: 152060 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00375

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000203 AC: 51 AN: 251492 AF XY: 0.000184

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000173

Gnomad ASJ exome AF: 0.00387

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000439

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000985 AC: 144 AN: 1461892 Hom.: 1 Cov.: 31 AF XY: 0.000103 AC XY: 75 AN XY: 727246

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.000112 AC: 5 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00348 AC: 91 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: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00156 AC: 9 AN: 5768

European-Non Finnish (NFE) AF: 0.0000180 AC: 20 AN: 1112010

Other (OTH) AF: 0.000315 AC: 19 AN: 60396

GnomAD4 genome AF: 0.000118 AC: 18 AN: 152178 Hom.: 0 Cov.: 31 AF XY: 0.000108 AC XY: 8 AN XY: 74410

African (AFR) AF: 0.00 AC: 0 AN: 41508

American (AMR) AF: 0.00 AC: 0 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00375 AC: 13 AN: 3468

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 4812

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10600

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68004

Other (OTH) AF: 0.00 AC: 0 AN: 2108

Alfa AF: 0.000224 Hom.: 0

Bravo AF: 0.000132

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	1	Charcot-Marie-Tooth disease type 4 (1)
-	-	1	Inborn genetic diseases (1)
-	-	1	NDRG1-related disorder (1)
-	1	-	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.87
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.37
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.36	T
Eigen	Benign	0.14
Eigen_PC	Benign	0.20
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.81	T
M_CAP	Benign	0.043	D
MetaRNN	Benign	0.17	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Uncertain	2.7	M
PhyloP100		5.9
PrimateAI	Uncertain	0.78	T
PROVEAN	Pathogenic	-5.0	D
REVEL	Benign	0.29
Sift	Uncertain	0.0060	D
Sift4G	Uncertain	0.0030	D
Varity_R		0.64
gMVP		0.85
Mutation Taster		=0/100	disease causing

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs143549909;

hg19: chr8-134262721;