7-124822964-C-T

Variant names:

• chr7-124822964-C-T
• rs530211997
• NM_015450.3:c.*998G>A

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS1

The NM_015450.3(POT1):​c.*998G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00229 in 166,000 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0024 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0015 (0 hom.)
• Consequence: POT1 NM_015450.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.502
• 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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 7-124822964-C-T is Benign according to our data. Variant chr7-124822964-C-T is described in ClinVar as [Benign]. Clinvar id is 2657976.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00236 (359/152156) while in subpopulation NFE AF = 0.00399 (271/67954). AF 95% confidence interval is 0.0036. There are 1 homozygotes in GnomAd4. There are 158 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
POT1	NM_015450.3	c.*998G>A		3_prime_UTR_variant	Exon 19 of 19	ENST00000357628.8	NP_056265.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
POT1	ENST00000357628.8	c.*998G>A		3_prime_UTR_variant	Exon 19 of 19	2	NM_015450.3	ENSP00000350249.3
POT1	ENST00000393329.5	c.*998G>A		3_prime_UTR_variant	Exon 18 of 18	5		ENSP00000377002.1
POT1	ENST00000430927.6	n.*425-413G>A		intron_variant	Intron 18 of 18	3		ENSP00000397632.2
POT1	ENST00000436534.5	n.392-413G>A		intron_variant	Intron 4 of 4	3

Frequencies

GnomAD3 genomes AF: 0.00236 AC: 359 AN: 152038 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000991

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00151

Gnomad ASJ AF: 0.000289

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00160

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00399

Gnomad OTH AF: 0.00287

GnomAD4 exome AF: 0.00152 AC: 21 AN: 13844 Hom.: 0 Cov.: 0 AF XY: 0.00136 AC XY: 10 AN XY: 7354

African (AFR) AF: 0.00 AC: 0 AN: 536

American (AMR) AF: 0.00143 AC: 3 AN: 2100

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 402

East Asian (EAS) AF: 0.00 AC: 0 AN: 1566

South Asian (SAS) AF: 0.000698 AC: 1 AN: 1432

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 392

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 20

European-Non Finnish (NFE) AF: 0.00246 AC: 17 AN: 6898

Other (OTH) AF: 0.00 AC: 0 AN: 498

GnomAD4 genome AF: 0.00236 AC: 359 AN: 152156 Hom.: 1 Cov.: 32 AF XY: 0.00212 AC XY: 158 AN XY: 74402

African (AFR) AF: 0.000988 AC: 41 AN: 41512

American (AMR) AF: 0.00150 AC: 23 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.000289 AC: 1 AN: 3462

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00160 AC: 17 AN: 10608

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00399 AC: 271 AN: 67954

Other (OTH) AF: 0.00284 AC: 6 AN: 2114

Alfa AF: 0.000319 Hom.: 0

Bravo AF: 0.00209

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Dec 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

POT1: BS1, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.51
DANN	Benign	0.52
PhyloP100		-0.50
Mutation Taster		=100/0	polymorphism

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: rs530211997; hg19: chr7-124463018;