7-124841129-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_015450.3(POT1):c.1213G>A(p.Ala405Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000548 in 1,460,766 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A405V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: POT1 NM_015450.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 0.310

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 Likely_benign. Variant got -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.09104028).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
POT1	NM_015450.3	c.1213G>A	p.Ala405Thr	missense_variant	14/19	ENST00000357628.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
POT1	ENST00000357628.8	c.1213G>A	p.Ala405Thr	missense_variant	14/19	2	NM_015450.3	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000797 AC: 2 AN: 250792 Hom.: 0 AF XY: 0.00000738 AC XY: 1 AN XY: 135550

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000579

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000548 AC: 8 AN: 1460766 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 726698

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000447

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000253

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

POT1-related disorder Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 26, 2022

The POT1 c.1213G>A variant is predicted to result in the amino acid substitution p.Ala405Thr. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0058% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/7-124481183-C-T). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 12, 2022

The p.A405T variant (also known as c.1213G>A), located in coding exon 10 of the POT1 gene, results from a G to A substitution at nucleotide position 1213. The alanine at codon 405 is replaced by threonine, an amino acid with similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Tumor predisposition syndrome 3 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jan 16, 2024

This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 405 of the POT1 protein (p.Ala405Thr). This variant is present in population databases (rs753851042, gnomAD 0.006%). 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: 475030). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.57
Cadd	Benign	11
Dann	Uncertain	0.98
DEOGEN2	Benign	0.16	T;T;T
Eigen	Benign	-0.74
Eigen_PC	Benign	-0.69
FATHMM_MKL	Benign	0.084	N
LIST_S2	Benign	0.77	T;T;.
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.091	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.7	L;.;.
MutationTaster	Benign	0.98	N;N
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.74	N;N;.
REVEL	Benign	0.028
Sift	Benign	0.13	T;T;.
Sift4G	Benign	0.13	T;T;T
Polyphen		0.0050	B;.;.
Vest4		0.14
MutPred		0.26		Loss of helix (P = 0.0558);.;.;
MVP		0.30
MPC		0.085
ClinPred		0.099	T
GERP RS		1.7
Varity_R		0.058
gMVP		0.41

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: rs753851042; hg19: chr7-124481183; COSMIC: COSV62927747;