chr7-124829280-G-T
Variant summary
Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_015450.3(POT1):c.1568C>A(p.Ser523*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. S523S) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_015450.3 stop_gained
Scores
Clinical Significance
Conservation
Publications
- pulmonary fibrosis and/or bone marrow failure syndrome, telomere-related, 8Inheritance: AD Classification: STRONG, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
- tumor predisposition syndrome 3Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
- glioma susceptibility 9Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
- thyroid gland carcinomaInheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
- cerebroretinal microangiopathy with calcifications and cysts 3Inheritance: AR Classification: LIMITED Submitted by: G2P, Ambry Genetics
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ACMG classification
Our verdict: Pathogenic. The variant received 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
POT1 | NM_015450.3 | c.1568C>A | p.Ser523* | stop_gained | Exon 16 of 19 | ENST00000357628.8 | NP_056265.2 |
Ensembl
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD2 exomes AF: 0.00000398 AC: 1AN: 251036 AF XY: 0.00 show subpopulations
GnomAD4 exome Cov.: 30
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Tumor predisposition syndrome 3 Pathogenic:1
This sequence change creates a premature translational stop signal (p.Ser523*) in the POT1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in POT1 are known to be pathogenic (PMID: 32155570). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with POT1-related conditions. ClinVar contains an entry for this variant (Variation ID: 1775415). Studies have shown that this premature translational stop signal is associated with inconclusive levels of altered splicing (Invitae). For these reasons, this variant has been classified as Pathogenic. -
Hereditary cancer-predisposing syndrome Pathogenic:1
The p.S523* pathogenic mutation (also known as c.1568C>A), located in coding exon 12 of the POT1 gene, results from a C to A substitution at nucleotide position 1568. This changes the amino acid from a serine to a stop codon within coding exon 12. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at