7-124842948-T-G

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_015450.3(POT1):c.1022A>C(p.Gln341Pro) variant causes a missense change. The variant allele was found at a frequency of 0.00000253 in 1,582,046 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. Q341K) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

POT1
NM_015450.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 3.94

Publications

1 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

POT1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
POT1	NM_015450.3 link	c.1022A>C	p.Gln341Pro	missense_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 link	c.1022A>C	p.Gln341Pro	missense_variant	Exon 13 of 19	2	NM_015450.3	ENSP00000350249.3

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152156

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:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000210

AC:

AN:

1429890

Hom.:

Cov.:

AF XY:

0.00000281

AC XY:

AN XY:

711266

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31564

American (AMR)

AF:

0.00

AC:

AN:

35782

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24944

East Asian (EAS)

AF:

0.00

AC:

AN:

38862

South Asian (SAS)

AF:

0.0000376

AC:

AN:

79820

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53006

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5650

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1101290

Other (OTH)

AF:

0.00

AC:

AN:

58972

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.558

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152156

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74342

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41440

American (AMR)

AF:

0.00

AC:

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5200

South Asian (SAS)

AF:

0.000207

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68008

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Tumor predisposition syndrome 3

Uncertain:1

Aug 18, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces glutamine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 341 of the POT1 protein (p.Gln341Pro). 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. 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. 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

Oct 31, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.Q341P variant (also known as c.1022A>C), located in coding exon 9 of the POT1 gene, results from an A to C substitution at nucleotide position 1022. The glutamine at codon 341 is replaced by proline, an amino acid with similar properties. This amino acid position is conserved. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this variant remains unclear.

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Uncertain

0.098

BayesDel_noAF

Benign

-0.10

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.17

T;T

Eigen

Uncertain

0.39

Eigen_PC

Uncertain

0.40

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.86

D;D

M_CAP

Benign

0.018

MetaRNN

Uncertain

0.67

D;D

MetaSVM

Benign

-0.86

MutationAssessor

Uncertain

2.6

M;.

PhyloP100

3.9

PrimateAI

Benign

0.44

PROVEAN

Benign

-1.1

N;N

REVEL

Benign

0.11

Sift

Benign

0.13

T;T

Sift4G

Uncertain

0.028

D;D

Vest4

0.82

ClinPred

0.88

GERP RS

5.6

Varity_R

0.70

gMVP

0.67

Mutation Taster

=68/32

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over