chr7-124892326-T-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBP6BS1

The NM_015450.3(POT1):c.64A>G(p.Ile22Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000252 in 1,539,338 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I22T) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00018 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00026 ( 0 hom. )

Consequence

POT1
NM_015450.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5B:5

Conservation

PhyloP100: -1.13

Publications

3 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 -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.027004272).

BP6

Variant 7-124892326-T-C is Benign according to our data. Variant chr7-124892326-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 436392.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000185 (28/151670) while in subpopulation NFE AF = 0.00034 (23/67642). AF 95% confidence interval is 0.000232. There are 0 homozygotes in GnomAd4. There are 13 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

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	UniProt
POT1	NM_015450.3	MANE Select	c.64A>G	p.Ile22Val	missense	Exon 6 of 19	NP_056265.2	Q9NUX5-1
POT1	NM_001042594.2		c.-199A>G		5_prime_UTR	Exon 6 of 18	NP_001036059.1	A8MTK3
POT1	NR_003102.2		n.507A>G		non_coding_transcript_exon	Exon 6 of 20

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
POT1	ENST00000357628.8	TSL:2 MANE Select	c.64A>G	p.Ile22Val	missense	Exon 6 of 19	ENSP00000350249.3	Q9NUX5-1
POT1	ENST00000607932.5	TSL:1	n.64A>G		non_coding_transcript_exon	Exon 2 of 14	ENSP00000476506.1	Q5MJ34
POT1	ENST00000608057.5	TSL:1	n.64A>G		non_coding_transcript_exon	Exon 2 of 16	ENSP00000476371.1	Q5MJ35

Frequencies

GnomAD3 genomes

AF:

0.000185

AC:

AN:

151552

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000725

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:

0.0000942

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000340

Gnomad OTH

AF:

0.000481

GnomAD2 exomes

AF:

0.000160

AC:

AN:

187696

AF XY:

0.000175

show subpopulations

Gnomad AFR exome

AF:

0.0000859

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000973

Gnomad NFE exome

AF:

0.000292

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000259

AC:

360

AN:

1387668

Hom.:

Cov.:

AF XY:

0.000253

AC XY:

174

AN XY:

688876

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

28342

American (AMR)

AF:

0.00

AC:

AN:

28652

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24058

East Asian (EAS)

AF:

0.00

AC:

AN:

34194

South Asian (SAS)

AF:

0.00

AC:

AN:

74206

European-Finnish (FIN)

AF:

0.0000569

AC:

AN:

52736

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5556

European-Non Finnish (NFE)

AF:

0.000326

AC:

353

AN:

1082648

Other (OTH)

AF:

0.0000698

AC:

AN:

57276

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.455

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

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

GnomAD4 genome

AF:

0.000185

AC:

AN:

151670

Hom.:

Cov.:

AF XY:

0.000175

AC XY:

AN XY:

74144

show subpopulations

African (AFR)

AF:

0.0000723

AC:

AN:

41488

American (AMR)

AF:

0.00

AC:

AN:

15154

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3462

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.0000942

AC:

AN:

10612

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000340

AC:

AN:

67642

Other (OTH)

AF:

0.000476

AC:

AN:

2100

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.487

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.000351

Hom.:

Bravo

AF:

0.000166

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.000132

AC:

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

not specified (3)

Hereditary cancer-predisposing syndrome (2)

Tumor predisposition syndrome 3 (1)

Tumor predisposition syndrome 3;C5830496:Pulmonary fibrosis and/or bone marrow failure syndrome, telomere-related, 8;C5830497:Cerebroretinal microangiopathy with calcifications and cysts 3 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.050

BayesDel_addAF

Benign

-0.46

BayesDel_noAF

Benign

-0.59

CADD

Benign

0.40

(source)

DANN

Benign

0.36

DEOGEN2

Benign

0.34

Eigen

Benign

-1.8

Eigen_PC

Benign

-1.7

FATHMM_MKL

Benign

0.050

LIST_S2

Benign

0.63

M_CAP

Benign

0.0039

MetaRNN

Benign

0.027

MetaSVM

Benign

-0.98

MutationAssessor

Benign

-0.63

PhyloP100

-1.1

PrimateAI

Benign

0.30

PROVEAN

Benign

0.12

REVEL

Benign

0.072

Sift

Benign

1.0

Sift4G

Benign

1.0

Polyphen

0.0

Vest4

0.087

MVP

0.21

MPC

0.74

ClinPred

0.0062

GERP RS

-7.0

Varity_R

0.048

gMVP

0.38

Mutation Taster

=89/11

polymorphism

(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

Computational scores

Splicing

Publications

Other links and lift over