rs797045169

Variant names:

• chr7-124840994-C-A
• rs797045169
• NM_015450.3:c.1348G>T

Your query was ambiguous. Multiple possible variants found:

• chr7-124840994-C-A
• chr7-124840994-C-T

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_015450.3(POT1):​c.1348G>T​(p.Glu450*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Synonymous variant affecting the same amino acid position (i.e. E450E) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: POT1 NM_015450.3 stop_gained
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 0.667
• Publications: 6 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: Pathogenic. The variant received 11 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 7-124840994-C-A is Pathogenic according to our data. Variant chr7-124840994-C-A is described in ClinVar as Pathogenic. ClinVar VariationId is 209094.Status of the report is no_assertion_criteria_provided, 0 stars.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POT1	NM_015450.3	MANE Select	c.1348G>T	p.Glu450*	stop_gained	Exon 14 of 19	NP_056265.2	Q9NUX5-1
	POT1	NM_001042594.2		c.955G>T	p.Glu319*	stop_gained	Exon 13 of 18	NP_001036059.1	A8MTK3
	POT1	NR_003102.2		n.1911G>T		non_coding_transcript_exon	Exon 15 of 20

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POT1	ENST00000357628.8	TSL:2 MANE Select	c.1348G>T	p.Glu450*	stop_gained	Exon 14 of 19	ENSP00000350249.3	Q9NUX5-1
	POT1	ENST00000607932.5	TSL:1	n.1348G>T		non_coding_transcript_exon	Exon 10 of 14	ENSP00000476506.1	Q5MJ34
	POT1	ENST00000608057.5	TSL:1	n.*445G>T		non_coding_transcript_exon	Exon 11 of 16	ENSP00000476371.1	Q5MJ35

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1455270 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 724390

African (AFR) AF: 0.00 AC: 0 AN: 33324

American (AMR) AF: 0.00 AC: 0 AN: 44698

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26058

East Asian (EAS) AF: 0.00 AC: 0 AN: 39542

South Asian (SAS) AF: 0.00 AC: 0 AN: 86022

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53056

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5332

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1107098

Other (OTH) AF: 0.00 AC: 0 AN: 60140

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Tumor predisposition syndrome 3 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.62	D
BayesDel_noAF	Pathogenic	0.58
CADD	Pathogenic	37
DANN	Uncertain	1.0
Eigen	Pathogenic	0.74
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Uncertain	0.91	D
PhyloP100		0.67
Vest4		0.92
GERP RS		3.5
Mutation Taster		=0/200	disease causing (fs/PTC)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs797045169; hg19: chr7-124481048;