7-124871040-A-T

Variant names:

• chr7-124871040-A-T
• NM_015450.3:c.126T>A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Moderate PP5_Moderate

The NM_015450.3(POT1):​c.126T>A​(p.Asp42Glu) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.000000703 in 1,422,960 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: POT1 NM_015450.3 missense, splice_region
• Scores: Splicing: ADA: 0.3210
• Clinical Significance: Likely pathogenic criteria provided, single submitter P: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 Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.88
• PP5: Variant 7-124871040-A-T is Pathogenic according to our data. Variant chr7-124871040-A-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 3668731.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
POT1	NM_015450.3	c.126T>A	p.Asp42Glu	missense_variant, splice_region_variant	Exon 7 of 19	ENST00000357628.8	NP_056265.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
POT1	ENST00000357628.8	c.126T>A	p.Asp42Glu	missense_variant, splice_region_variant	Exon 7 of 19	2	NM_015450.3	ENSP00000350249.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.03e-7 AC: 1 AN: 1422960 Hom.: 0 Cov.: 29 AF XY: 0.00000141 AC XY: 1 AN XY: 707190

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.14e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Tumor predisposition syndrome 3 Pathogenic:1

Oct 07, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 missense change has been observed in individuals with POT1-related conditions (external communication, internal data). 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. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

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	0.94	D
LIST_S2	Benign	0.83	T;.;D
M_CAP	Benign	0.052	D
MetaRNN	Pathogenic	0.88	D;D;D
MetaSVM	Benign	-0.30	T
MutationAssessor	Uncertain	2.4	M;.;.
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
Varity_R		0.77
gMVP		0.84

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.32
dbscSNV1_RF	Benign	0.46
SpliceAI score (max)		0.18		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: chr7-124511094;