rs1554429221

Positions:

• chr7-124871040-A-C
• chr7-124871040-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PP3_Moderate PP5

The NM_015450.3(POT1):​c.126T>G​(p.Asp42Glu) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: not found (cov: 33)
• Consequence: POT1 NM_015450.3 missense, splice_region
• Scores: Splicing: ADA: 0.4643
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1
• Conservation: PhyloP100: 5.99

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 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.878
• PP5: Variant 7-124871040-A-C is Pathogenic according to our data. Variant chr7-124871040-A-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 475035.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
POT1	NM_015450.3	c.126T>G	p.Asp42Glu	missense_variant, splice_region_variant	7/19	ENST00000357628.8	NP_056265.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
POT1	ENST00000357628.8	c.126T>G	p.Asp42Glu	missense_variant, splice_region_variant	7/19	2	NM_015450.3	ENSP00000350249	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 33

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hereditary cancer-predisposing syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 18, 2023

The p.D42E variant (also known as c.126T>G), located in coding exon 3 of the POT1 gene, results from a T to G substitution at nucleotide position 126. The aspartic acid at codon 42 is replaced by glutamic acid, an amino acid with highly similar properties. This alteration has been observed in multiple individuals with a personal and/or family history that is consistent with POT1-related disease and was shown to segregate with disease in at least one family (Ambry internal data). This amino acid position is highly conserved in available vertebrate species. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Tumor predisposition syndrome 3 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 16, 2023

This sequence change replaces aspartic acid, which is acidic and polar, with glutamic acid, which is acidic and polar, at codon 42 of the POT1 protein (p.Asp42Glu). 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: 475035). 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 disruptive. 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	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.040
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.89	D;D;D
Eigen	Uncertain	0.45
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.83	T;.;D
M_CAP	Benign	0.051	D
MetaRNN	Pathogenic	0.88	D;D;D
MetaSVM	Benign	-0.30	T
MutationAssessor	Uncertain	2.4	M;.;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.63	T
PROVEAN	Uncertain	-3.5	D;D;.
REVEL	Uncertain	0.54
Sift	Benign	0.052	T;T;.
Sift4G	Pathogenic	0.0	D;.;.
Polyphen		0.64	P;.;.
Vest4		0.85
MutPred		0.80		Gain of ubiquitination at K39 (P = 0.0804);Gain of ubiquitination at K39 (P = 0.0804);Gain of ubiquitination at K39 (P = 0.0804);
MVP		0.88
MPC		1.7
ClinPred		0.98	D
GERP RS		5.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.77
gMVP		0.84

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.46
dbscSNV1_RF	Benign	0.50
SpliceAI score (max)		0.24		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.24		Position offset: 1

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

Publications

LitVar

Other links and lift over

dbSNP: rs1554429221; hg19: chr7-124511094; COSMIC: COSV104423893;