NM_015450.3:c.256-3056A>G

Variant names:

• chr7-124866696-T-C
• rs6973812
• NM_015450.3:c.256-3056A>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.256-3056A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.601 in 152,012 control chromosomes in the GnomAD database, including 27,610 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 0.60 (27610 hom., cov: 32)
• Consequence: POT1 NM_015450.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.593
• Publications: 5 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=-0.94).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.641 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.256-3056A>G		intron	N/A	NP_056265.2
	POT1	NM_001042594.2		c.-138-3056A>G		intron	N/A	NP_001036059.1
	POT1	NR_003102.2		n.699-3056A>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.256-3056A>G		intron	N/A	ENSP00000350249.3
	POT1	ENST00000607932.5	TSL:1	n.256-3056A>G		intron	N/A	ENSP00000476506.1
	POT1	ENST00000608057.5	TSL:1	n.256-3056A>G		intron	N/A	ENSP00000476371.1

Frequencies

GnomAD3 genomes AF: 0.601 AC: 91332 AN: 151894 Hom.: 27588 Cov.: 32

Gnomad AFR AF: 0.648

Gnomad AMI AF: 0.454

Gnomad AMR AF: 0.572

Gnomad ASJ AF: 0.601

Gnomad EAS AF: 0.505

Gnomad SAS AF: 0.614

Gnomad FIN AF: 0.498

Gnomad MID AF: 0.615

Gnomad NFE AF: 0.605

Gnomad OTH AF: 0.572

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

GnomAD4 genome AF: 0.601 AC: 91398 AN: 152012 Hom.: 27610 Cov.: 32 AF XY: 0.598 AC XY: 44406 AN XY: 74270

African (AFR) AF: 0.648 AC: 26864 AN: 41484

American (AMR) AF: 0.571 AC: 8718 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.601 AC: 2085 AN: 3468

East Asian (EAS) AF: 0.504 AC: 2590 AN: 5140

South Asian (SAS) AF: 0.614 AC: 2961 AN: 4820

European-Finnish (FIN) AF: 0.498 AC: 5260 AN: 10562

Middle Eastern (MID) AF: 0.606 AC: 177 AN: 292

European-Non Finnish (NFE) AF: 0.605 AC: 41121 AN: 67958

Other (OTH) AF: 0.573 AC: 1210 AN: 2112

Alfa AF: 0.612 Hom.: 14725

Bravo AF: 0.605

Asia WGS AF: 0.585 AC: 2037 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	0.80
DANN	Benign	0.82
PhyloP100		-0.59
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: rs6973812; hg19: chr7-124506750;