7-124823966-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_015450.3(POT1):c.1901T>C(p.Ile634Thr) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts 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. I634M) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: POT1 NM_015450.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.53

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.19746733).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
POT1	NM_015450.3	c.1901T>C	p.Ile634Thr	missense_variant	19/19	ENST00000357628.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
POT1	ENST00000357628.8	c.1901T>C	p.Ile634Thr	missense_variant	19/19	2	NM_015450.3	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 27

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Tumor predisposition syndrome 3 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Sep 01, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Benign	-0.019	T
BayesDel_noAF	Benign	-0.26
Cadd	Benign	20
Dann	Uncertain	1.0
DEOGEN2	Benign	0.18	T;T
Eigen	Uncertain	0.37
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.88	D;D
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.20	T;T
MetaSVM	Benign	-0.82	T
MutationAssessor	Uncertain	2.6	M;.
MutationTaster	Benign	0.99	N;N
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-0.98	N;N
REVEL	Benign	0.14
Sift	Uncertain	0.0030	D;D
Sift4G	Uncertain	0.010	D;D
Polyphen		0.80	P;.
Vest4		0.14
MutPred		0.35		Loss of stability (P = 0.0027);.;
MVP		0.39
MPC		0.14
ClinPred		0.78	D
GERP RS		5.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.51
gMVP		0.23

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr7-124464020;