7-124827416-T-C

Variant names:

• chr7-124827416-T-C
• rs10244817
• NM_015450.3:c.1595-111A>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.1595-111A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.254 in 477,982 control chromosomes in the GnomAD database, including 16,258 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.22 (4044 hom., cov: 32)
  • Exomes 𝑓: 0.27 (12214 hom.)
• Consequence: POT1 NM_015450.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.0490
• Publications: 10 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=-0.87).
• BP6: Variant 7-124827416-T-C is Benign according to our data. Variant chr7-124827416-T-C is described in ClinVar as Benign. ClinVar VariationId is 677025.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.29 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
POT1	NM_015450.3	c.1595-111A>G		intron_variant	Intron 16 of 18	ENST00000357628.8	NP_056265.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
POT1	ENST00000357628.8	c.1595-111A>G		intron_variant	Intron 16 of 18	2	NM_015450.3	ENSP00000350249.3

Frequencies

GnomAD3 genomes AF: 0.218 AC: 33105 AN: 152016 Hom.: 4047 Cov.: 32

Gnomad AFR AF: 0.112

Gnomad AMI AF: 0.262

Gnomad AMR AF: 0.191

Gnomad ASJ AF: 0.282

Gnomad EAS AF: 0.303

Gnomad SAS AF: 0.184

Gnomad FIN AF: 0.200

Gnomad MID AF: 0.228

Gnomad NFE AF: 0.283

Gnomad OTH AF: 0.214

GnomAD4 exome AF: 0.271 AC: 88438 AN: 325848 Hom.: 12214 AF XY: 0.273 AC XY: 46053 AN XY: 168852

African (AFR) AF: 0.112 AC: 875 AN: 7834

American (AMR) AF: 0.184 AC: 1464 AN: 7960

Ashkenazi Jewish (ASJ) AF: 0.280 AC: 2555 AN: 9122

East Asian (EAS) AF: 0.331 AC: 7218 AN: 21822

South Asian (SAS) AF: 0.194 AC: 1466 AN: 7572

European-Finnish (FIN) AF: 0.225 AC: 7665 AN: 34034

Middle Eastern (MID) AF: 0.267 AC: 565 AN: 2116

European-Non Finnish (NFE) AF: 0.286 AC: 62180 AN: 217634

Other (OTH) AF: 0.251 AC: 4450 AN: 17754

GnomAD4 genome AF: 0.218 AC: 33091 AN: 152134 Hom.: 4044 Cov.: 32 AF XY: 0.213 AC XY: 15848 AN XY: 74362

African (AFR) AF: 0.111 AC: 4629 AN: 41556

American (AMR) AF: 0.191 AC: 2917 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.282 AC: 979 AN: 3470

East Asian (EAS) AF: 0.302 AC: 1558 AN: 5158

South Asian (SAS) AF: 0.184 AC: 887 AN: 4820

European-Finnish (FIN) AF: 0.200 AC: 2120 AN: 10576

Middle Eastern (MID) AF: 0.218 AC: 64 AN: 294

European-Non Finnish (NFE) AF: 0.283 AC: 19251 AN: 67958

Other (OTH) AF: 0.213 AC: 448 AN: 2104

Alfa AF: 0.256 Hom.: 1840

Bravo AF: 0.215

Asia WGS AF: 0.228 AC: 792 AN: 3478

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 15, 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	-0.87
CADD	Benign	0.56
DANN	Benign	0.77
PhyloP100		0.049
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: rs10244817; hg19: chr7-124467470;