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

Genomes: not found (cov: 32)

Consequence

POT1
NM_015450.3 stop_gained

Scores

2
2
3

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:2

Conservation

PhyloP100: 1.95

Publications

2 publications found
Variant links:
Genes affected
POT1 (HGNC:17284): (protection of telomeres 1) This gene is a member of the telombin family and encodes a nuclear protein involved in telomere maintenance. Specifically, this protein functions as a member of a multi-protein complex that binds to the TTAGGG repeats of telomeres, regulating telomere length and protecting chromosome ends from illegitimate recombination, catastrophic chromosome instability, and abnormal chromosome segregation. Increased transcriptional expression of this gene is associated with stomach carcinogenesis and its progression. Alternatively spliced transcript variants have been described. [provided by RefSeq, Jul 2008]
POT1 Gene-Disease associations (from GenCC):
  • pulmonary fibrosis and/or bone marrow failure syndrome, telomere-related, 8
    Inheritance: AD Classification: STRONG, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
  • tumor predisposition syndrome 3
    Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
  • glioma susceptibility 9
    Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
  • thyroid gland carcinoma
    Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
  • cerebroretinal microangiopathy with calcifications and cysts 3
    Inheritance: AR Classification: LIMITED Submitted by: G2P, Ambry Genetics

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 18 ACMG points.

PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 7-124829280-G-T is Pathogenic according to our data. Variant chr7-124829280-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 1775415.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
POT1NM_015450.3 linkc.1568C>A p.Ser523* stop_gained Exon 16 of 19 ENST00000357628.8 NP_056265.2 Q9NUX5-1A0A024R739

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
POT1ENST00000357628.8 linkc.1568C>A p.Ser523* stop_gained Exon 16 of 19 2 NM_015450.3 ENSP00000350249.3 Q9NUX5-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD2 exomes
AF:
0.00000398
AC:
1
AN:
251036
AF XY:
0.00
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.000164
GnomAD4 exome
Cov.:
30
GnomAD4 genome
Cov.:
32
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000116
AC:
1

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Tumor predisposition syndrome 3 Pathogenic:1
May 27, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

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
Jun 02, 2022
Ambry Genetics
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

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: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.62
D
BayesDel_noAF
Pathogenic
0.43
CADD
Pathogenic
35
DANN
Uncertain
0.99
Eigen
Uncertain
0.31
Eigen_PC
Benign
0.060
FATHMM_MKL
Benign
0.43
N
PhyloP100
1.9
Vest4
0.88
GERP RS
4.2
Mutation Taster
=3/197
disease causing (fs/PTC)

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.42
Details are displayed if max score is > 0.2
DS_DL_spliceai
0.42
Position offset: -26

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

Other links and lift over

dbSNP: rs139388603; hg19: chr7-124469334; API