rs201959970

Variant names:

• chr8-133238962-G-A
• rs201959970
• NM_006096.4:c.1101C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Moderate BP6 BP7 BS1 BS2

The ENST00000323851.13(NDRG1):​c.1101C>T​(p.Ser367Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000174 in 1,583,170 control chromosomes in the GnomAD database, including 2 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 0.00013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00018 (2 hom.)
• Consequence: NDRG1 ENST00000323851.13 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:4
• Conservation: PhyloP100: 0.0390
• 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: Orphanet, Labcorp Genetics (formerly Invitae), Illumina

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.46).
• BP6: Variant 8-133238962-G-A is Benign according to our data. Variant chr8-133238962-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 447748.
• BP7: Synonymous conserved (PhyloP=0.039 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000131 (20/152288) while in subpopulation SAS AF = 0.00186 (9/4832). AF 95% confidence interval is 0.000971. There are 0 homozygotes in GnomAd4. There are 12 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 2 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000323851.13. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NDRG1	NM_006096.4	MANE Select	c.1101C>T	p.Ser367Ser	synonymous	Exon 16 of 16	NP_006087.2
	NDRG1	NM_001374844.1		c.1152C>T	p.Ser384Ser	synonymous	Exon 16 of 16	NP_001361773.1
	NDRG1	NM_001135242.2		c.1101C>T	p.Ser367Ser	synonymous	Exon 16 of 16	NP_001128714.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NDRG1	ENST00000323851.13	TSL:1 MANE Select	c.1101C>T	p.Ser367Ser	synonymous	Exon 16 of 16	ENSP00000319977.8
	NDRG1	ENST00000522476.5	TSL:1	c.903C>T	p.Ser301Ser	synonymous	Exon 14 of 14	ENSP00000427894.1
	NDRG1	ENST00000414097.6	TSL:2	c.1101C>T	p.Ser367Ser	synonymous	Exon 16 of 16	ENSP00000404854.2

Frequencies

GnomAD3 genomes AF: 0.000125 AC: 19 AN: 152170 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00165

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000162

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000301 AC: 59 AN: 196220 AF XY: 0.000398

Gnomad AFR exome AF: 0.0000868

Gnomad AMR exome AF: 0.0000356

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000210

Gnomad OTH exome AF: 0.000199

GnomAD4 exome AF: 0.000178 AC: 255 AN: 1430882 Hom.: 2 Cov.: 30 AF XY: 0.000236 AC XY: 167 AN XY: 708602

African (AFR) AF: 0.0000301 AC: 1 AN: 33198

American (AMR) AF: 0.0000256 AC: 1 AN: 39084

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25430

East Asian (EAS) AF: 0.00 AC: 0 AN: 38580

South Asian (SAS) AF: 0.00149 AC: 122 AN: 81610

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50284

Middle Eastern (MID) AF: 0.000534 AC: 3 AN: 5618

European-Non Finnish (NFE) AF: 0.000106 AC: 116 AN: 1097868

Other (OTH) AF: 0.000203 AC: 12 AN: 59210

GnomAD4 genome AF: 0.000131 AC: 20 AN: 152288 Hom.: 0 Cov.: 32 AF XY: 0.000161 AC XY: 12 AN XY: 74466

African (AFR) AF: 0.00 AC: 0 AN: 41564

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

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

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

South Asian (SAS) AF: 0.00186 AC: 9 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

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

European-Non Finnish (NFE) AF: 0.000162 AC: 11 AN: 68012

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.000248 Hom.: 0

Bravo AF: 0.0000642

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.46
CADD	Benign	11
DANN	Benign	0.92
PhyloP100		0.039
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
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: rs201959970; hg19: chr8-134251205;