Genetic Variant POT1:p.Gly404Val (chr7-124841131-C-A) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_015450.3(POT1):c.1211G>T(p.Gly404Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.014 in 1,612,590 control chromosomes in the GnomAD database, including 242 homozygotes. 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 Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G404D) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.011 ( 25 hom., cov: 32)

Exomes 𝑓: 0.014 ( 217 hom. )

Consequence

POT1
NM_015450.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: 0.0320

Publications

17 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: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0021687746).

BP6

Variant 7-124841131-C-A is Benign according to our data. Variant chr7-124841131-C-A is described in ClinVar as Benign. ClinVar VariationId is 475029.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0107 (1624/151974) while in subpopulation NFE AF = 0.0144 (976/67828). AF 95% confidence interval is 0.0136. There are 25 homozygotes in GnomAd4. There are 821 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 25 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015450.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
POT1	NM_015450.3	MANE Select	c.1211G>T	p.Gly404Val	missense	Exon 14 of 19	NP_056265.2
POT1	NM_001042594.2		c.818G>T	p.Gly273Val	missense	Exon 13 of 18	NP_001036059.1
POT1	NR_003102.2		n.1774G>T		non_coding_transcript_exon	Exon 15 of 20

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
POT1	ENST00000357628.8	TSL:2 MANE Select	c.1211G>T	p.Gly404Val	missense	Exon 14 of 19	ENSP00000350249.3
POT1	ENST00000607932.5	TSL:1	n.1211G>T		non_coding_transcript_exon	Exon 10 of 14	ENSP00000476506.1
POT1	ENST00000608057.5	TSL:1	n.*308G>T		non_coding_transcript_exon	Exon 11 of 16	ENSP00000476371.1

Frequencies

GnomAD3 genomes

AF:

0.0107

AC:

1626

AN:

151856

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00239

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.00505

Gnomad ASJ

AF:

0.0690

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0104

Gnomad FIN

AF:

0.0151

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.0144

Gnomad OTH

AF:

0.0101

GnomAD2 exomes

AF:

0.0136

AC:

3422

AN:

250782

AF XY:

0.0142

show subpopulations

Gnomad AFR exome

AF:

0.00253

Gnomad AMR exome

AF:

0.00359

Gnomad ASJ exome

AF:

0.0663

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0143

Gnomad NFE exome

AF:

0.0161

Gnomad OTH exome

AF:

0.0154

GnomAD4 exome

AF:

0.0144

AC:

20998

AN:

1460616

Hom.:

217

Cov.:

AF XY:

0.0145

AC XY:

10540

AN XY:

726642

show subpopulations

African (AFR)

AF:

0.00251

AC:

AN:

33448

American (AMR)

AF:

0.00324

AC:

145

AN:

44712

Ashkenazi Jewish (ASJ)

AF:

0.0687

AC:

1793

AN:

26088

East Asian (EAS)

AF:

0.0000506

AC:

AN:

39558

South Asian (SAS)

AF:

0.0136

AC:

1172

AN:

86140

European-Finnish (FIN)

AF:

0.0136

AC:

725

AN:

53348

Middle Eastern (MID)

AF:

0.0170

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.0144

AC:

16039

AN:

1111226

Other (OTH)

AF:

0.0156

AC:

940

AN:

60334

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.459

Heterozygous variant carriers

1001

2001

3002

4002

5003

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

630

1260

1890

2520

3150

<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:

0.0107

AC:

1624

AN:

151974

Hom.:

Cov.:

AF XY:

0.0111

AC XY:

821

AN XY:

74296

show subpopulations

African (AFR)

AF:

0.00238

AC:

AN:

41534

American (AMR)

AF:

0.00504

AC:

AN:

15268

Ashkenazi Jewish (ASJ)

AF:

0.0690

AC:

239

AN:

3462

East Asian (EAS)

AF:

0.00

AC:

AN:

5170

South Asian (SAS)

AF:

0.0104

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.0151

AC:

160

AN:

10576

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0144

AC:

976

AN:

67828

Other (OTH)

AF:

0.00950

AC:

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

170

254

339

424

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0143

Hom.:

Bravo

AF:

0.00972

TwinsUK

AF:

0.0105

AC:

ALSPAC

AF:

0.0143

AC:

ESP6500AA

AF:

0.00272

AC:

ESP6500EA

AF:

0.0163

AC:

140

ExAC

AF:

0.0136

AC:

1646

Asia WGS

AF:

0.00289

AC:

AN:

3476

EpiCase

AF:

0.0151

EpiControl

AF:

0.0155

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Apr 02, 2021

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Dec 28, 2017

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

not provided

Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

Sep 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

POT1: BP4, BS1, BS2

Nov 03, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Tumor predisposition syndrome 3

Benign:2

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Aug 05, 2021

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Hereditary cancer-predisposing syndrome

Benign:1

Dec 14, 2016

Ambry Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.096

BayesDel_addAF

Benign

-0.60

BayesDel_noAF

Benign

-0.61

CADD

Benign

(source)

DANN

Benign

0.79

DEOGEN2

Benign

0.20

Eigen

Benign

-0.82

Eigen_PC

Benign

-0.85

FATHMM_MKL

Benign

0.042

LIST_S2

Benign

0.69

MetaRNN

Benign

0.0022

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.6

PhyloP100

0.032

PrimateAI

Benign

0.26

PROVEAN

Benign

-1.1

REVEL

Benign

0.058

Sift

Benign

0.052

Sift4G

Benign

0.21

Polyphen

0.0020

Vest4

0.12

MPC

0.11

ClinPred

0.0086

GERP RS

-1.5

Varity_R

0.092

gMVP

0.67

Mutation Taster

=97/3

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over