rs750470470

Variant names:

• chr7-124842898-G-GA
• rs750470470
• NM_015450.3:c.1071dupT

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_015450.3(POT1):​c.1071dupT​(p.Gln358SerfsTer13) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000503 in 1,608,962 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000053 (0 hom.)
• Consequence: POT1 NM_015450.3 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 0.510

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]

ACMG classification

Verdict is Pathogenic. Variant got 16 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 7-124842898-G-GA is Pathogenic according to our data. Variant chr7-124842898-G-GA is described in ClinVar as [Likely_pathogenic]. Clinvar id is 541864.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
POT1	NM_015450.3	c.1071dupT	p.Gln358SerfsTer13	frameshift_variant	Exon 13 of 19	ENST00000357628.8	NP_056265.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
POT1	ENST00000357628.8	c.1071dupT	p.Gln358SerfsTer13	frameshift_variant	Exon 13 of 19	2	NM_015450.3	ENSP00000350249.3

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152040 Hom.: 0 Cov.: 32

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: 0.0000588

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000364 AC: 9 AN: 247366 Hom.: 0 AF XY: 0.0000299 AC XY: 4 AN XY: 133990

Gnomad AFR exome AF: 0.0000621

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000710

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000529 AC: 77 AN: 1456922 Hom.: 0 Cov.: 30 AF XY: 0.0000538 AC XY: 39 AN XY: 724936

Gnomad4 AFR exome AF: 0.0000301

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: 0.0000667

Gnomad4 OTH exome AF: 0.0000332

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152040 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74258

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: 0.0000588

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000680 Hom.: 0

Bravo AF: 0.0000227

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Tumor predisposition syndrome 3 Pathogenic:3

Nov 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.Gln358Serfs*13) 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 present in population databases (rs750470470, gnomAD 0.007%). This premature translational stop signal has been observed in individual(s) with chronic lymphocytic leukemia and/or colorectal cancer (PMID: 27528712, 29625052). ClinVar contains an entry for this variant (Variation ID: 541864). For these reasons, this variant has been classified as Pathogenic. -

Jun 24, 2021

St. Jude Molecular Pathology, St. Jude Children's Research Hospital

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The POT1 c.1071dup (p.Gln358SerfsTer13) change causes a frameshift and the creation of a premature stop codon. This change is predicted to cause protein truncation or absence of the protein due to nonsense mediated decay (PVS1). This variant has a maximum subpopulation frequency of 0.0071% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/variant/7-124482952-G-GA). This variant has been reported in two affected siblings in a kindred with familial chronic lymphocytic leukemia (PS4_Supporting; PMID: 27528712). In summary, this variant meets criteria to be classified as likely pathogenic based on the ACMG/AMP criteria: PVS1, PS4. -

Mar 04, 2025

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Criteria applied: PVS1,PS4_MOD -

Hereditary cancer-predisposing syndrome Pathogenic:2

Oct 14, 2021

Sema4, Sema4

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

- -

Sep 13, 2024

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1071dupT pathogenic mutation, located in coding exon 9 of the POT1 gene, results from a duplication of T at nucleotide position 1071, causing a translational frameshift with a predicted alternate stop codon (p.Q358Sfs*13).This alteration has been reported in two siblings with chronic lymphyocytic leukemia (Speedy HE et al. Blood, 2016 11;128:2319-2326). In addition to the clinical data presented in the literature, 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. -

Long telomere syndrome Pathogenic:1

Apr 01, 2023

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

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

not provided Pathogenic:1

Aug 14, 2023

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 29625052, 27528712, 32987645, 36656928, 32155570, 36451132) -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs750470470; hg19: chr7-124482952;