rs1554426915

Variant names:

• chr7-124863459-G-A
• rs1554426915
• NM_015450.3:c.437C>T

Your query was ambiguous. Multiple possible variants found:

• chr7-124863459-G-A
• chr7-124863459-G-C
• chr7-124863459-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_015450.3(POT1):​c.437C>T​(p.Pro146Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: POT1 NM_015450.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: 3.65

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.19960171).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
POT1	NM_015450.3	c.437C>T	p.Pro146Leu	missense_variant	Exon 8 of 19	ENST00000357628.8	NP_056265.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
POT1	ENST00000357628.8	c.437C>T	p.Pro146Leu	missense_variant	Exon 8 of 19	2	NM_015450.3	ENSP00000350249.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Nov 02, 2016

Genetic Services Laboratory, University of Chicago

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Tumor predisposition syndrome 3 Uncertain:1

Jan 13, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 146 of the POT1 protein (p.Pro146Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with aplastic anemia and shortened telomeres (PMID: 30523342). ClinVar contains an entry for this variant (Variation ID: 436390). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt POT1 protein function with a negative predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Hereditary cancer-predisposing syndrome Uncertain:1

Sep 23, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.P146L variant (also known as c.437C>T), located in coding exon 4 of the POT1 gene, results from a C to T substitution at nucleotide position 437. The proline at codon 146 is replaced by leucine, an amino acid with similar properties. This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear. -

Dyskeratosis congenita Uncertain:1

-

Bone Marrow Failure laboratory, Queen Mary University London

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: research

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.089
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	20
DANN	Benign	0.91
DEOGEN2	Benign	0.18	T;T
Eigen	Benign	0.052
Eigen_PC	Benign	0.21
FATHMM_MKL	Benign	0.57	D
LIST_S2	Uncertain	0.94	D;D
M_CAP	Benign	0.0098	T
MetaRNN	Benign	0.20	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.3	M;.
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-1.4	N;N
REVEL	Benign	0.11
Sift	Benign	0.30	T;T
Sift4G	Benign	0.31	T;T
Polyphen		0.22	B;.
Vest4		0.16
MutPred		0.45		Gain of catalytic residue at P146 (P = 0.0028);.;
MVP		0.43
MPC		0.90
ClinPred		0.55	D
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.12
gMVP		0.66

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: rs1554426915; hg19: chr7-124503513;