rs61755062

Variant names:

• chr8-133247893-C-T
• rs61755062
• NM_006096.4:c.789G>A

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_Moderate BP6 BS1 BS2

The NM_006096.4(NDRG1):​c.789G>A​(p.Ser263Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00151 in 1,614,098 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. S263S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0010 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0016 (4 hom.)
• Consequence: NDRG1 NM_006096.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:11
• Conservation: PhyloP100: -0.0660
• Publications: 2 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 -11 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.46).
• BP6: Variant 8-133247893-C-T is Benign according to our data. Variant chr8-133247893-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 379907.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.001 (153/152324) while in subpopulation NFE AF = 0.00172 (117/68028). AF 95% confidence interval is 0.00147. There are 0 homozygotes in GnomAd4. There are 69 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 4 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.789G>A	p.Ser263Ser	synonymous	Exon 12 of 16	NP_006087.2
	NDRG1	NM_001374844.1		c.840G>A	p.Ser280Ser	synonymous	Exon 12 of 16	NP_001361773.1
	NDRG1	NM_001135242.2		c.789G>A	p.Ser263Ser	synonymous	Exon 12 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.789G>A	p.Ser263Ser	synonymous	Exon 12 of 16	ENSP00000319977.8	Q92597-1
	NDRG1	ENST00000522476.5	TSL:1	c.591G>A	p.Ser197Ser	synonymous	Exon 10 of 14	ENSP00000427894.1	Q92597-2
	NDRG1	ENST00000414097.6	TSL:2	c.789G>A	p.Ser263Ser	synonymous	Exon 12 of 16	ENSP00000404854.2	Q92597-1

Frequencies

GnomAD3 genomes AF: 0.00101 AC: 153 AN: 152206 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000603

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000458

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00172

Gnomad OTH AF: 0.000956

GnomAD2 exomes AF: 0.000958 AC: 241 AN: 251476 AF XY: 0.000949

Gnomad AFR exome AF: 0.000554

Gnomad AMR exome AF: 0.000549

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000139

Gnomad NFE exome AF: 0.00171

Gnomad OTH exome AF: 0.000651

GnomAD4 exome AF: 0.00156 AC: 2279 AN: 1461774 Hom.: 4 Cov.: 31 AF XY: 0.00158 AC XY: 1151 AN XY: 727194

African (AFR) AF: 0.000478 AC: 16 AN: 33476

American (AMR) AF: 0.000514 AC: 23 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.000243 AC: 21 AN: 86250

European-Finnish (FIN) AF: 0.0000936 AC: 5 AN: 53410

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5704

European-Non Finnish (NFE) AF: 0.00188 AC: 2090 AN: 1111994

Other (OTH) AF: 0.00205 AC: 124 AN: 60384

GnomAD4 genome AF: 0.00100 AC: 153 AN: 152324 Hom.: 0 Cov.: 33 AF XY: 0.000926 AC XY: 69 AN XY: 74478

African (AFR) AF: 0.000601 AC: 25 AN: 41570

American (AMR) AF: 0.000457 AC: 7 AN: 15306

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

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

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

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

European-Non Finnish (NFE) AF: 0.00172 AC: 117 AN: 68028

Other (OTH) AF: 0.000946 AC: 2 AN: 2114

Alfa AF: 0.00144 Hom.: 1

Bravo AF: 0.00114

EpiCase AF: 0.00164

EpiControl AF: 0.00207

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	1	1	Charcot-Marie-Tooth disease type 4D (2)
-	-	2	not specified (2)
-	-	1	Charcot-Marie-Tooth disease (1)
-	-	1	Charcot-Marie-Tooth disease type 4 (1)
-	-	1	Inborn genetic diseases (1)
-	-	1	NDRG1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.46
CADD	Benign	5.3
DANN	Benign	0.61
PhyloP100		-0.066
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.6
Mutation Taster		=89/11	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: rs61755062; hg19: chr8-134260136;