rs765621411
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PVS1_StrongPM2
The NM_006096.4(NDRG1):c.1051C>T(p.Arg351Ter) variant causes a stop gained change. The variant allele was found at a frequency of 0.0000463 in 1,598,292 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. R351R) has been classified as Likely benign.
Frequency
Consequence
NM_006096.4 stop_gained
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
NDRG1 | NM_006096.4 | c.1051C>T | p.Arg351Ter | stop_gained | 16/16 | ENST00000323851.13 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NDRG1 | ENST00000323851.13 | c.1051C>T | p.Arg351Ter | stop_gained | 16/16 | 1 | NM_006096.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000789 AC: 12AN: 152058Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000918 AC: 20AN: 217764Hom.: 1 AF XY: 0.000110 AC XY: 13AN XY: 117910
GnomAD4 exome AF: 0.0000429 AC: 62AN: 1446234Hom.: 1 Cov.: 30 AF XY: 0.0000432 AC XY: 31AN XY: 717754
GnomAD4 genome ? AF: 0.0000789 AC: 12AN: 152058Hom.: 0 Cov.: 32 AF XY: 0.000148 AC XY: 11AN XY: 74270
ClinVar
Submissions by phenotype
Charcot-Marie-Tooth disease type 4 Uncertain:2
Uncertain significance, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jul 26, 2022 | This sequence change creates a premature translational stop signal (p.Arg351*) in the NDRG1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 44 amino acid(s) of the NDRG1 protein. This variant is present in population databases (rs765621411, gnomAD 0.07%), including at least one homozygous and/or hemizygous individual. This variant has not been reported in the literature in individuals affected with NDRG1-related conditions. ClinVar contains an entry for this variant (Variation ID: 240289). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jul 14, 2022 | Variant summary: NDRG1 c.1051C>T (p.Arg351X) results in a premature termination codon in the last exon of the gene, therefore it is not expected to cause nonsense mediated decay (NMD), but is predicted to cause a truncation of the encoded protein, removing amino acids 351 to 394 (InterPro). No truncations downstream of this position have been reported in affected individuals (HGMD). The variant allele was found at a frequency of 9.2e-05 in 217764 control chromosomes in the gnomAD database, including 1 homozygote. To our knowledge, no occurrence of c.1051C>T in individuals affected with Charcot-Marie Disease Type 4D and no experimental evidence demonstrating its impact on protein function have been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014, and both of them classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at