dbSNP rs762019631: POT1:p.Ser461Cys (chr7-124835403-T-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_015450.3(POT1):c.1381A>T(p.Ser461Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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 Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S461R) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Consequence

POT1
NM_015450.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.122

Publications

0 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: Labcorp Genetics (formerly Invitae), Ambry Genetics
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: Ambry Genetics, G2P

POT1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.088359386).

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.1381A>T	p.Ser461Cys	missense	Exon 15 of 19	NP_056265.2	Q9NUX5-1
POT1	NM_001042594.2		c.988A>T	p.Ser330Cys	missense	Exon 14 of 18	NP_001036059.1	A8MTK3
POT1	NR_003102.2		n.1944A>T		non_coding_transcript_exon	Exon 16 of 20

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
POT1	ENST00000357628.8	TSL:2 MANE Select	c.1381A>T	p.Ser461Cys	missense	Exon 15 of 19	ENSP00000350249.3	Q9NUX5-1
POT1	ENST00000607932.5	TSL:1	n.1381A>T		non_coding_transcript_exon	Exon 11 of 14	ENSP00000476506.1	Q5MJ34
POT1	ENST00000608057.5	TSL:1	n.*478A>T		non_coding_transcript_exon	Exon 12 of 16	ENSP00000476371.1	Q5MJ35

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000398

AC:

AN:

251282

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000880

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000824

AC:

ClinVar

ClinVar submissions as Germline

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Tumor predisposition syndrome 3 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.097

BayesDel_addAF

Benign

-0.31

BayesDel_noAF

Benign

-0.68

CADD

Benign

9.6

(source)

DANN

Benign

0.86

DEOGEN2

Benign

0.085

Eigen

Benign

-0.74

Eigen_PC

Benign

-0.63

FATHMM_MKL

Benign

0.076

LIST_S2

Benign

0.67

M_CAP

Benign

0.0028

MetaRNN

Benign

0.088

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.5

PhyloP100

-0.12

PrimateAI

Benign

0.29

PROVEAN

Benign

-0.37

REVEL

Benign

0.064

Sift

Benign

0.18

Sift4G

Benign

0.098

Polyphen

0.0

Vest4

0.18

MutPred

0.28

Loss of helix (P = 0.079)

MVP

0.21

MPC

0.081

ClinPred

0.091

GERP RS

0.50

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.14

gMVP

0.39

Mutation Taster

=83/17

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

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over