chr8-133264546-C-G
Variant summary
Our verdict is Pathogenic. Variant got 22 ACMG points: 22P and 0B. PVS1PM2PP3_StrongPP5_Very_Strong
The NM_006096.4(NDRG1):c.205+1G>C variant causes a splice donor change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000616 in 1,461,422 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Consequence
NM_006096.4 splice_donor
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 22 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
NDRG1 | NM_006096.4 | c.205+1G>C | splice_donor_variant | ENST00000323851.13 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NDRG1 | ENST00000323851.13 | c.205+1G>C | splice_donor_variant | 1 | NM_006096.4 | P1 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD4 exome AF: 0.00000616 AC: 9AN: 1461422Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1AN XY: 727038
GnomAD4 genome Cov.: 33
ClinVar
Submissions by phenotype
Inborn genetic diseases Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Sep 08, 2021 | The c.205+1G>C intronic variant results from a G to C substitution one nucleotide after coding exon 3 of the NDRG1 gene. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as likely pathogenic. - |
Charcot-Marie-Tooth disease type 4 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Oct 28, 2022 | For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. Disruption of this splice site has been observed in individuals with clinical features of NDRG1-related conditions (PMID: 34169998; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change affects a donor splice site in intron 4 of the NDRG1 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in NDRG1 are known to be pathogenic (PMID: 12872253, 23996628). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at