7-124854411-T-C

Variant names:

• chr7-124854411-T-C
• rs12532038
• NM_015450.3:c.703-1273A>G

Variant summary

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

The NM_015450.3(POT1):​c.703-1273A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.383 in 151,698 control chromosomes in the GnomAD database, including 11,856 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 0.38 (11856 hom., cov: 32)
• Consequence: POT1 NM_015450.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.27
• Publications: 2 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=-1.11).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.53 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
POT1	NM_015450.3	c.703-1273A>G		intron_variant	Intron 9 of 18	ENST00000357628.8	NP_056265.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
POT1	ENST00000357628.8	c.703-1273A>G		intron_variant	Intron 9 of 18	2	NM_015450.3	ENSP00000350249.3

Frequencies

GnomAD3 genomes AF: 0.383 AC: 58036 AN: 151576 Hom.: 11827 Cov.: 32

Gnomad AFR AF: 0.535

Gnomad AMI AF: 0.193

Gnomad AMR AF: 0.380

Gnomad ASJ AF: 0.319

Gnomad EAS AF: 0.201

Gnomad SAS AF: 0.427

Gnomad FIN AF: 0.296

Gnomad MID AF: 0.379

Gnomad NFE AF: 0.322

Gnomad OTH AF: 0.357

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

GnomAD4 genome AF: 0.383 AC: 58119 AN: 151698 Hom.: 11856 Cov.: 32 AF XY: 0.384 AC XY: 28467 AN XY: 74138

African (AFR) AF: 0.536 AC: 22164 AN: 41386

American (AMR) AF: 0.380 AC: 5794 AN: 15250

Ashkenazi Jewish (ASJ) AF: 0.319 AC: 1107 AN: 3466

East Asian (EAS) AF: 0.201 AC: 1035 AN: 5158

South Asian (SAS) AF: 0.427 AC: 2053 AN: 4810

European-Finnish (FIN) AF: 0.296 AC: 3125 AN: 10546

Middle Eastern (MID) AF: 0.384 AC: 113 AN: 294

European-Non Finnish (NFE) AF: 0.322 AC: 21794 AN: 67770

Other (OTH) AF: 0.360 AC: 758 AN: 2108

Alfa AF: 0.350 Hom.: 3712

Bravo AF: 0.390

Asia WGS AF: 0.354 AC: 1232 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.1
CADD	Benign	0.065
DANN	Benign	0.19
PhyloP100		-2.3
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs12532038; hg19: chr7-124494465;