rs4360236

Variant names:

• chr7-124886685-C-T
• rs4360236
• NM_015450.3:c.124+5581G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_015450.3(POT1):​c.124+5581G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.184 in 151,856 control chromosomes in the GnomAD database, including 3,095 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.18 (3095 hom., cov: 32)
• Consequence: POT1 NM_015450.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.12
• 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.298 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
POT1	NM_015450.3	c.124+5581G>A		intron_variant	Intron 6 of 18	ENST00000357628.8	NP_056265.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
POT1	ENST00000357628.8	c.124+5581G>A		intron_variant	Intron 6 of 18	2	NM_015450.3	ENSP00000350249.3

Frequencies

GnomAD3 genomes AF: 0.183 AC: 27828 AN: 151738 Hom.: 3090 Cov.: 32

Gnomad AFR AF: 0.303

Gnomad AMI AF: 0.0899

Gnomad AMR AF: 0.234

Gnomad ASJ AF: 0.130

Gnomad EAS AF: 0.200

Gnomad SAS AF: 0.294

Gnomad FIN AF: 0.100

Gnomad MID AF: 0.158

Gnomad NFE AF: 0.108

Gnomad OTH AF: 0.168

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.184 AC: 27867 AN: 151856 Hom.: 3095 Cov.: 32 AF XY: 0.188 AC XY: 13941 AN XY: 74206

African (AFR) AF: 0.302 AC: 12522 AN: 41404

American (AMR) AF: 0.234 AC: 3565 AN: 15246

Ashkenazi Jewish (ASJ) AF: 0.130 AC: 450 AN: 3464

East Asian (EAS) AF: 0.200 AC: 1033 AN: 5160

South Asian (SAS) AF: 0.293 AC: 1409 AN: 4806

European-Finnish (FIN) AF: 0.100 AC: 1060 AN: 10566

Middle Eastern (MID) AF: 0.163 AC: 48 AN: 294

European-Non Finnish (NFE) AF: 0.108 AC: 7332 AN: 67896

Other (OTH) AF: 0.174 AC: 366 AN: 2108

Alfa AF: 0.136 Hom.: 3695

Bravo AF: 0.194

Asia WGS AF: 0.272 AC: 944 AN: 3464

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	3.7
DANN	Benign	0.53
PhyloP100		1.1
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: rs4360236; hg19: chr7-124526739;