rs770890978

Variant names:

• chr7-124859115-G-A
• rs770890978
• NM_015450.3:c.547-3C>T

Your query was ambiguous. Multiple possible variants found:

• chr7-124859115-G-A
• chr7-124859115-G-T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_015450.3(POT1):​c.547-3C>T variant causes a splice region, intron change. The variant allele was found at a frequency of 0.00000142 in 1,412,976 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: POT1 NM_015450.3 splice_region, intron
• Scores: Splicing: ADA: 0.01699
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 3.94
• Publications: 0 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.52).

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.547-3C>T		splice_region intron	N/A	NP_056265.2
	POT1	NM_001042594.2		c.154-3C>T		splice_region intron	N/A	NP_001036059.1
	POT1	NR_003102.2		n.990-3C>T		splice_region intron	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POT1	ENST00000357628.8	TSL:2 MANE Select	c.547-3C>T		splice_region intron	N/A	ENSP00000350249.3
	POT1	ENST00000607932.5	TSL:1	n.547-3C>T		splice_region intron	N/A	ENSP00000476506.1
	POT1	ENST00000608057.5	TSL:1	n.547-3C>T		splice_region intron	N/A	ENSP00000476371.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000142 AC: 2 AN: 1412976 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 700950

African (AFR) AF: 0.00 AC: 0 AN: 32158

American (AMR) AF: 0.00 AC: 0 AN: 40116

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24722

East Asian (EAS) AF: 0.00 AC: 0 AN: 38520

South Asian (SAS) AF: 0.00 AC: 0 AN: 75502

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51864

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5560

European-Non Finnish (NFE) AF: 0.00000184 AC: 2 AN: 1086508

Other (OTH) AF: 0.00 AC: 0 AN: 58026

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Hereditary cancer-predisposing syndrome (1)
-	1	-	Tumor predisposition syndrome 3 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.52
CADD	Benign	13
DANN	Benign	0.63
PhyloP100		3.9
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.017
dbscSNV1_RF	Benign	0.16
SpliceAI score (max)		0.57		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.57		Position offset: -3

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs770890978; hg19: chr7-124499169;