rs7784168

Variant names:

• chr7-124851984-T-C
• rs7784168
• NM_015450.3:c.870-33A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_015450.3(POT1):​c.870-33A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.317 in 1,406,024 control chromosomes in the GnomAD database, including 72,118 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.32 (7704 hom., cov: 33)
  • Exomes 𝑓: 0.32 (64414 hom.)
• Consequence: POT1 NM_015450.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.722
• Publications: 19 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.72).
• BP6: Variant 7-124851984-T-C is Benign according to our data. Variant chr7-124851984-T-C is described in ClinVar as [Benign]. Clinvar id is 677012.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.381 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
POT1	NM_015450.3	c.870-33A>G		intron_variant	Intron 10 of 18	ENST00000357628.8	NP_056265.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
POT1	ENST00000357628.8	c.870-33A>G		intron_variant	Intron 10 of 18	2	NM_015450.3	ENSP00000350249.3

Frequencies

GnomAD3 genomes AF: 0.318 AC: 48275 AN: 151934 Hom.: 7700 Cov.: 33

Gnomad AFR AF: 0.340

Gnomad AMI AF: 0.193

Gnomad AMR AF: 0.340

Gnomad ASJ AF: 0.293

Gnomad EAS AF: 0.201

Gnomad SAS AF: 0.395

Gnomad FIN AF: 0.294

Gnomad MID AF: 0.297

Gnomad NFE AF: 0.310

Gnomad OTH AF: 0.292

GnomAD2 exomes AF: 0.323 AC: 75446 AN: 233736 AF XY: 0.323

Gnomad AFR exome AF: 0.343

Gnomad AMR exome AF: 0.377

Gnomad ASJ exome AF: 0.287

Gnomad EAS exome AF: 0.205

Gnomad FIN exome AF: 0.290

Gnomad NFE exome AF: 0.316

Gnomad OTH exome AF: 0.308

GnomAD4 exome AF: 0.317 AC: 397648 AN: 1253972 Hom.: 64414 Cov.: 17 AF XY: 0.319 AC XY: 201971 AN XY: 633462

African (AFR) AF: 0.346 AC: 10014 AN: 28950

American (AMR) AF: 0.367 AC: 15404 AN: 42018

Ashkenazi Jewish (ASJ) AF: 0.285 AC: 6982 AN: 24512

East Asian (EAS) AF: 0.211 AC: 8106 AN: 38498

South Asian (SAS) AF: 0.387 AC: 30596 AN: 79050

European-Finnish (FIN) AF: 0.292 AC: 15472 AN: 52910

Middle Eastern (MID) AF: 0.320 AC: 1537 AN: 4806

European-Non Finnish (NFE) AF: 0.315 AC: 292981 AN: 929768

Other (OTH) AF: 0.310 AC: 16556 AN: 53460

GnomAD4 genome AF: 0.318 AC: 48306 AN: 152052 Hom.: 7704 Cov.: 33 AF XY: 0.319 AC XY: 23734 AN XY: 74316

African (AFR) AF: 0.340 AC: 14089 AN: 41484

American (AMR) AF: 0.340 AC: 5201 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.293 AC: 1016 AN: 3468

East Asian (EAS) AF: 0.201 AC: 1039 AN: 5178

South Asian (SAS) AF: 0.395 AC: 1908 AN: 4826

European-Finnish (FIN) AF: 0.294 AC: 3104 AN: 10564

Middle Eastern (MID) AF: 0.303 AC: 89 AN: 294

European-Non Finnish (NFE) AF: 0.310 AC: 21063 AN: 67924

Other (OTH) AF: 0.294 AC: 621 AN: 2114

Alfa AF: 0.318 Hom.: 5543

Bravo AF: 0.317

Asia WGS AF: 0.318 AC: 1107 AN: 3472

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 20, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.72
CADD	Benign	0.98
DANN	Benign	0.90
PhyloP100		-0.72
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs7784168; hg19: chr7-124492038; COSMIC: COSV62930379;