7-124823983-T-G

Variant names:

• chr7-124823983-T-G
• rs17147565
• NM_015450.3:c.1884A>C

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_015450.3(POT1):​c.1884A>C​(p.Thr628Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0059 in 1,588,362 control chromosomes in the GnomAD database, including 477 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.031 (250 hom., cov: 32)
  • Exomes 𝑓: 0.0032 (227 hom.)
• Consequence: POT1 NM_015450.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.252
• Publications: 7 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.039).
• BP6: Variant 7-124823983-T-G is Benign according to our data. Variant chr7-124823983-T-G is described in ClinVar as Benign. ClinVar VariationId is 475068.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.252 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.106 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.1884A>C	p.Thr628Thr	synonymous	Exon 19 of 19	NP_056265.2
	POT1	NM_001042594.2		c.1491A>C	p.Thr497Thr	synonymous	Exon 18 of 18	NP_001036059.1
	POT1	NR_003102.2		n.2447A>C		non_coding_transcript_exon	Exon 20 of 20

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POT1	ENST00000357628.8	TSL:2 MANE Select	c.1884A>C	p.Thr628Thr	synonymous	Exon 19 of 19	ENSP00000350249.3
	POT1	ENST00000607932.5	TSL:1	n.*238A>C		non_coding_transcript_exon	Exon 14 of 14	ENSP00000476506.1
	POT1	ENST00000608057.5	TSL:1	n.*981A>C		non_coding_transcript_exon	Exon 16 of 16	ENSP00000476371.1

Frequencies

GnomAD3 genomes AF: 0.0313 AC: 4752 AN: 151990 Hom.: 250 Cov.: 32

Gnomad AFR AF: 0.108

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000250

Gnomad OTH AF: 0.0236

GnomAD2 exomes AF: 0.00806 AC: 1997 AN: 247744 AF XY: 0.00605

Gnomad AFR exome AF: 0.112

Gnomad AMR exome AF: 0.00481

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000169

Gnomad OTH exome AF: 0.00385

GnomAD4 exome AF: 0.00321 AC: 4607 AN: 1436254 Hom.: 227 Cov.: 29 AF XY: 0.00273 AC XY: 1957 AN XY: 715748

African (AFR) AF: 0.118 AC: 3852 AN: 32746

American (AMR) AF: 0.00525 AC: 233 AN: 44366

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25936

East Asian (EAS) AF: 0.00 AC: 0 AN: 39412

South Asian (SAS) AF: 0.000270 AC: 23 AN: 85228

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53316

Middle Eastern (MID) AF: 0.00350 AC: 20 AN: 5712

European-Non Finnish (NFE) AF: 0.0000835 AC: 91 AN: 1090064

Other (OTH) AF: 0.00652 AC: 388 AN: 59474

GnomAD4 genome AF: 0.0313 AC: 4763 AN: 152108 Hom.: 250 Cov.: 32 AF XY: 0.0304 AC XY: 2259 AN XY: 74372

African (AFR) AF: 0.108 AC: 4496 AN: 41510

American (AMR) AF: 0.0130 AC: 199 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

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

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000250 AC: 17 AN: 67938

Other (OTH) AF: 0.0233 AC: 49 AN: 2100

Alfa AF: 0.0160 Hom.: 110

Bravo AF: 0.0366

Asia WGS AF: 0.00491 AC: 17 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	1	Hereditary cancer-predisposing syndrome (1)
-	-	1	not provided (1)
-	-	1	Tumor predisposition syndrome 3 (1)
-	-	1	Tumor predisposition syndrome 3;C5830496:Pulmonary fibrosis and/or bone marrow failure syndrome, telomere-related, 8;C5830497:Cerebroretinal microangiopathy with calcifications and cysts 3 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.49
CADD	Benign	6.5
DANN	Benign	0.75
PhyloP100		0.25
Mutation Taster		=99/1	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: rs17147565; hg19: chr7-124464037;