rs866612394

Positions:

chr7-124841179-C-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong

The NM_015450.3(POT1):c.1164-1G>A variant causes a splice acceptor, intron change. The variant allele was found at a frequency of 0.0000398 in 1,609,146 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

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000042 ( 0 hom. )

Consequence

POT1
NM_015450.3 splice_acceptor, intron

Scores

Splicing: ADA: 1.000

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7

Conservation

PhyloP100: 5.12

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 links:

POT1 (HGNC:):

POT1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 16 ACMG points.

PVS1

Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, Cryptic splice site detected, with MaxEntScore 7.6, offset of 43, new splice context is: atttggatataatttttcAGgat. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.

PP5

Variant 7-124841179-C-T is Pathogenic according to our data. Variant chr7-124841179-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 475026.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
POT1	NM_015450.3 linkuse as main transcript	c.1164-1G>A		splice_acceptor_variant, intron_variant		ENST00000357628.8	NP_056265.2	Q9NUX5-1A0A024R739

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
POT1	ENST00000357628.8 linkuse as main transcript	c.1164-1G>A		splice_acceptor_variant, intron_variant		2	NM_015450.3	ENSP00000350249.3		Q9NUX5-1

Frequencies

GnomAD3 genomes

AF:

0.0000198

AC:

AN:

151808

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000442

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000419

AC:

AN:

1457338

Hom.:

Cov.:

AF XY:

0.0000304

AC XY:

AN XY:

724786

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000550

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000198

AC:

AN:

151808

Hom.:

Cov.:

AF XY:

0.0000270

AC XY:

AN XY:

74136

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000442

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000440

Hom.:

Bravo

AF:

0.0000302

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Tumor predisposition syndrome 3

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 16, 2024	This sequence change affects an acceptor splice site in intron 13 of the POT1 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or disrupted protein product. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. Disruption of this splice site has been observed in individual(s) with clinical features of POT1 tumor predisposition syndrome (PMID: 27528712, 29625052). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 475026). Studies have shown that disruption of this splice site results in partial exon deletion and introduces a premature termination codon (PMID: 27528712; Invitae). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	St. Jude Molecular Pathology, St. Jude Children's Research Hospital	Nov 29, 2023	The POT1 c.1164-1G>A intronic change results in a G to A substitution at the -1 position of intron 13 of the POT1 gene and is predicted to disrupt the acceptor splice site. This variant has been reported in individual(s) with familial melanoma (PMID: 36876055). In a large case-control study, this variant was reported in 3 of 2928 individuals with cutaneous melanoma and was not detected in 3298 controls (PMID: 36539277). This variant was also found to co-segregate with chronic lymphocytic leukemia in a family in which three individuals were affected (PMID: 27528712). Finally, it has also been observed in 1 individual with hairy cell leukemia (PMID: 34193977). This variant has a maximum subpopulation frequency of 0.0065% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). In summary, this variant meets criteria to be classified as pathogenic. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Sep 25, 2023	- -

not provided

Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Nov 19, 2021	DNA sequence analysis of the POT1 gene demonstrated a sequence change in the canonical splice acceptor site in intron 13, c.1164-1G>A. This sequence change has been previously described in three family members with chronic lymphocytic leukemia (PMID: 27528712). Abnormal splicing product was detected by RT-PCR using cDNA from an individual carrying the c.1164-1G>A change (PMID: 27528712). This sequence change has been described in the gnomAD database in one individual which corresponds to a population frequency of 0.0032 % (dbSNP rs866612394). This sequence change is predicted to affect normal splicing of the POT1 gene and result in an abnormal protein. These collective evidences indicate that this sequence change is likely pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Apr 05, 2024	Canonical splice site variant demonstrated to cause aberrant splicing of exon 14 resulting in a null allele in a gene for which loss of function is a known mechanism of disease (PMID: 27528712); Observed in multiple affected individuals in a familial chronic lymphocytic leukemia kindred, as well as in other individuals with cutaneous melanoma or leukemia in published literature (PMID: 27528712, 29625052, 34193977, 36451132, 36876055); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 30877237, 27528712, 29625052, 34218205, 36451132, 34193977, 34482403, 37140166, 36876055) -

Long telomere syndrome

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

The Telomere Center at Johns Hopkins, Johns Hopkins University School of Medicine

Aug 01, 2022

- -

Hereditary cancer-predisposing syndrome

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 03, 2023

The c.1164-1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide upstream from coding exon 10 of the POT1 gene. In one study, whole exome sequencing performed in familial CLL cases identified c.1164-1G>A in three siblings with CLL; their father with non-Hodgkin's lymphoma was not tested. RNA analysis on the proband with this mutation, also designated as 7:g.124481233C>T, confirmed an abnormal splicing product occurring from an alternative splice acceptor site 43 bp downstream (Speedy HE et al. Blood 2016 11;128:2319-2326). In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site and may result in the creation or strengthening of a novel splice acceptor site; however direct evidence is insufficient at this time (Ambry internal data). In addition to the clinical data presented in the literature, 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 a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.62

BayesDel_noAF

Pathogenic

0.25

CADD

Pathogenic

DANN

Uncertain

0.99

Eigen

Pathogenic

0.99

Eigen_PC

Pathogenic

0.82

FATHMM_MKL

Uncertain

0.94

GERP RS

4.7

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.94

SpliceAI score (max)

0.95

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.47

Position offset: -44

DS_AL_spliceai

0.95

Position offset: -1

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over