rs753638532

Variant names:

• chr7-124853138-C-A
• rs753638532
• NM_015450.3:c.703G>T

Your query was ambiguous. Multiple possible variants found:

• chr7-124853138-C-A
• chr7-124853138-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_015450.3(POT1):​c.703G>T​(p.Val235Phe) variant causes a missense, splice region 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. 2/3 splice prediction tools predict no significant impact on normal splicing. 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. V235I) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: POT1 NM_015450.3 missense, splice_region
• Scores: Splicing: ADA: 0.8940
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 0.138
• Publications: 0 publications found

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

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.40789038).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
POT1	NM_015450.3	c.703G>T	p.Val235Phe	missense_variant, splice_region_variant	Exon 10 of 19	ENST00000357628.8	NP_056265.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
POT1	ENST00000357628.8	c.703G>T	p.Val235Phe	missense_variant, splice_region_variant	Exon 10 of 19	2	NM_015450.3	ENSP00000350249.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000213 AC: 3 AN: 1405312 Hom.: 0 Cov.: 28 AF XY: 0.00000143 AC XY: 1 AN XY: 699514

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 31074

American (AMR) AF: 0.0000265 AC: 1 AN: 37694

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24506

East Asian (EAS) AF: 0.00 AC: 0 AN: 39096

South Asian (SAS) AF: 0.0000126 AC: 1 AN: 79456

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52892

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5560

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1076790

Other (OTH) AF: 0.0000172 AC: 1 AN: 58244

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:1

Sep 19, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.V235F variant (also known as c.703G>T) is located in coding exon 6 of the POT1 gene. The valine at codon 235 is replaced by phenylalanine, an amino acid with highly similar properties. This change occurs in the first base pair of coding exon 6. This amino acid position is conserved. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Tumor predisposition syndrome 3 Uncertain:1

Jul 03, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces valine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 235 of the POT1 protein (p.Val235Phe). 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. ClinVar contains an entry for this variant (Variation ID: 1756835). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.31
BayesDel_addAF	Benign	-0.077	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.91	D;D
Eigen	Benign	0.057
Eigen_PC	Benign	0.074
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Uncertain	0.91	D;D
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.41	T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Uncertain	2.2	M;.
PhyloP100		0.14
PrimateAI	Benign	0.34	T
PROVEAN	Uncertain	-2.7	D;D
REVEL	Benign	0.11
Sift	Benign	0.036	D;D
Sift4G	Uncertain	0.044	D;D
Polyphen		0.84	P;.
Vest4		0.42
MutPred		0.30		Loss of sheet (P = 0.0357);.;
MVP		0.50
MPC		1.2
ClinPred		0.81	D
GERP RS		2.0
Varity_R		0.29
gMVP		0.66
Mutation Taster		=50/50

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.89
dbscSNV1_RF	Benign	0.64
SpliceAI score (max)		0.47		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.47		Position offset: 0

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

Other links and lift over

dbSNP: rs753638532; hg19: chr7-124493192;