rs7801661

Variant names:

• chr7-124843168-T-C
• rs7801661
• NM_015450.3:c.1007-205A>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.1007-205A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.247 in 362,668 control chromosomes in the GnomAD database, including 11,939 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.22 (4045 hom., cov: 32)
  • Exomes 𝑓: 0.27 (7894 hom.)
• Consequence: POT1 NM_015450.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.497
• Publications: 9 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=-0.82).
• BP6: Variant 7-124843168-T-C is Benign according to our data. Variant chr7-124843168-T-C is described in ClinVar as Benign. ClinVar VariationId is 677024.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.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POT1	NM_015450.3	MANE Select	c.1007-205A>G		intron	N/A	NP_056265.2
	POT1	NM_001042594.2		c.614-205A>G		intron	N/A	NP_001036059.1
	POT1	NR_003102.2		n.1570-205A>G		intron	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POT1	ENST00000357628.8	TSL:2 MANE Select	c.1007-205A>G		intron	N/A	ENSP00000350249.3
	POT1	ENST00000607932.5	TSL:1	n.1007-205A>G		intron	N/A	ENSP00000476506.1
	POT1	ENST00000608057.5	TSL:1	n.*104-205A>G		intron	N/A	ENSP00000476371.1

Frequencies

GnomAD3 genomes AF: 0.218 AC: 33155 AN: 151938 Hom.: 4048 Cov.: 32

Gnomad AFR AF: 0.113

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: 0.201

Gnomad MID AF: 0.231

Gnomad NFE AF: 0.283

Gnomad OTH AF: 0.214

GnomAD4 exome AF: 0.269 AC: 56572 AN: 210612 Hom.: 7894 Cov.: 3 AF XY: 0.270 AC XY: 29158 AN XY: 107986

African (AFR) AF: 0.115 AC: 728 AN: 6334

American (AMR) AF: 0.186 AC: 1270 AN: 6814

Ashkenazi Jewish (ASJ) AF: 0.275 AC: 2221 AN: 8062

East Asian (EAS) AF: 0.331 AC: 6213 AN: 18762

South Asian (SAS) AF: 0.179 AC: 705 AN: 3936

European-Finnish (FIN) AF: 0.226 AC: 3434 AN: 15188

Middle Eastern (MID) AF: 0.281 AC: 322 AN: 1144

European-Non Finnish (NFE) AF: 0.281 AC: 38301 AN: 136494

Other (OTH) AF: 0.243 AC: 3378 AN: 13878

GnomAD4 genome AF: 0.218 AC: 33142 AN: 152056 Hom.: 4045 Cov.: 32 AF XY: 0.214 AC XY: 15892 AN XY: 74340

African (AFR) AF: 0.113 AC: 4692 AN: 41504

American (AMR) AF: 0.190 AC: 2907 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.282 AC: 980 AN: 3472

East Asian (EAS) AF: 0.302 AC: 1562 AN: 5164

South Asian (SAS) AF: 0.185 AC: 888 AN: 4810

European-Finnish (FIN) AF: 0.201 AC: 2122 AN: 10570

Middle Eastern (MID) AF: 0.221 AC: 65 AN: 294

European-Non Finnish (NFE) AF: 0.283 AC: 19239 AN: 67950

Other (OTH) AF: 0.213 AC: 449 AN: 2106

Alfa AF: 0.263 Hom.: 4198

Bravo AF: 0.215

Asia WGS AF: 0.230 AC: 796 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 v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	5.3
DANN	Benign	0.70
PhyloP100		0.50
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: rs7801661; hg19: chr7-124483222; COSMIC: COSV62928764; COSMIC: COSV62928764;