5-1253803-C-T

Variant names:

• chr5-1253803-C-T
• rs35033501
• NM_198253.3:c.3324G>A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_198253.3(TERT):​c.3324G>A​(p.Pro1108Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0222 in 1,611,298 control chromosomes in the GnomAD database, including 513 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. P1108P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.018 (43 hom., cov: 33)
  • Exomes 𝑓: 0.023 (470 hom.)
• Consequence: TERT NM_198253.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:14
• Conservation: PhyloP100: -4.79
• Publications: 18 publications found

Genes affected

TERT (HGNC:11730): (telomerase reverse transcriptase) Telomerase is a ribonucleoprotein polymerase that maintains telomere ends by addition of the telomere repeat TTAGGG. The enzyme consists of a protein component with reverse transcriptase activity, encoded by this gene, and an RNA component which serves as a template for the telomere repeat. Telomerase expression plays a role in cellular senescence, as it is normally repressed in postnatal somatic cells resulting in progressive shortening of telomeres. Deregulation of telomerase expression in somatic cells may be involved in oncogenesis. Studies in mouse suggest that telomerase also participates in chromosomal repair, since de novo synthesis of telomere repeats may occur at double-stranded breaks. Alternatively spliced variants encoding different isoforms of telomerase reverse transcriptase have been identified; the full-length sequence of some variants has not been determined. Alternative splicing at this locus is thought to be one mechanism of regulation of telomerase activity. [provided by RefSeq, Jul 2008]

TERT Gene-Disease associations (from GenCC):

• pulmonary fibrosis and/or bone marrow failure, Telomere-related, 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), Ambry Genetics
• dyskeratosis congenita, autosomal dominant 2

  Inheritance: Unknown, SD, AD, AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Laboratory for Molecular Medicine, ClinGen, Genomics England PanelApp, G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae), PanelApp Australia
• acute myeloid leukemia

  Inheritance: AD Classification: STRONG, LIMITED Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• dyskeratosis congenita

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Hoyeraal-Hreidarsson syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• melanoma, cutaneous malignant, susceptibility to, 9

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)

ENSG00000287486 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 5-1253803-C-T is Benign according to our data. Variant chr5-1253803-C-T is described in ClinVar as Benign. ClinVar VariationId is 165375.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-4.79 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0179 (2723/152330) while in subpopulation NFE AF = 0.0267 (1813/68022). AF 95% confidence interval is 0.0256. There are 43 homozygotes in GnomAd4. There are 1333 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 43 AR,AD,SD,Unknown gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_198253.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TERT	NM_198253.3	MANE Select	c.3324G>A	p.Pro1108Pro	synonymous	Exon 16 of 16	NP_937983.2	O14746-1
	TERT	NM_001193376.3		c.3135G>A	p.Pro1045Pro	synonymous	Exon 15 of 15	NP_001180305.1	O14746-3
	TERT	NR_149162.3		n.3032G>A		non_coding_transcript_exon	Exon 13 of 13

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TERT	ENST00000310581.10	TSL:1 MANE Select	c.3324G>A	p.Pro1108Pro	synonymous	Exon 16 of 16	ENSP00000309572.5	O14746-1
	TERT	ENST00000334602.10	TSL:1	c.3135G>A	p.Pro1045Pro	synonymous	Exon 15 of 15	ENSP00000334346.6	O14746-3
	TERT	ENST00000460137.6	TSL:1	n.*529G>A		non_coding_transcript_exon	Exon 13 of 13	ENSP00000425003.1	O14746-4

Frequencies

GnomAD3 genomes AF: 0.0179 AC: 2722 AN: 152212 Hom.: 43 Cov.: 33

Gnomad AFR AF: 0.00388

Gnomad AMI AF: 0.0548

Gnomad AMR AF: 0.00556

Gnomad ASJ AF: 0.00403

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.0529

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0266

Gnomad OTH AF: 0.0143

GnomAD2 exomes AF: 0.0176 AC: 4264 AN: 241596 AF XY: 0.0168

Gnomad AFR exome AF: 0.00344

Gnomad AMR exome AF: 0.00379

Gnomad ASJ exome AF: 0.00423

Gnomad EAS exome AF: 0.000339

Gnomad FIN exome AF: 0.0564

Gnomad NFE exome AF: 0.0247

Gnomad OTH exome AF: 0.0164

GnomAD4 exome AF: 0.0227 AC: 33089 AN: 1458968 Hom.: 470 Cov.: 31 AF XY: 0.0223 AC XY: 16159 AN XY: 725546

African (AFR) AF: 0.00269 AC: 90 AN: 33472

American (AMR) AF: 0.00409 AC: 182 AN: 44548

Ashkenazi Jewish (ASJ) AF: 0.00494 AC: 128 AN: 25916

East Asian (EAS) AF: 0.000151 AC: 6 AN: 39652

South Asian (SAS) AF: 0.00240 AC: 205 AN: 85556

European-Finnish (FIN) AF: 0.0553 AC: 2894 AN: 52296

Middle Eastern (MID) AF: 0.00226 AC: 13 AN: 5764

European-Non Finnish (NFE) AF: 0.0257 AC: 28519 AN: 1111476

Other (OTH) AF: 0.0174 AC: 1052 AN: 60288

GnomAD4 genome AF: 0.0179 AC: 2723 AN: 152330 Hom.: 43 Cov.: 33 AF XY: 0.0179 AC XY: 1333 AN XY: 74468

African (AFR) AF: 0.00387 AC: 161 AN: 41580

American (AMR) AF: 0.00555 AC: 85 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00403 AC: 14 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00145 AC: 7 AN: 4830

European-Finnish (FIN) AF: 0.0529 AC: 562 AN: 10622

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

European-Non Finnish (NFE) AF: 0.0267 AC: 1813 AN: 68022

Other (OTH) AF: 0.0142 AC: 30 AN: 2116

Alfa AF: 0.0220 Hom.: 43

Bravo AF: 0.0136

Asia WGS AF: 0.00173 AC: 6 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	4	not provided (4)
-	-	1	Aplastic anemia (1)
-	-	1	Dyskeratosis congenita (1)
-	-	1	Dyskeratosis congenita, autosomal dominant 2 (1)
-	-	1	Idiopathic Pulmonary Fibrosis;C3151443:Dyskeratosis congenita, autosomal dominant 2 (1)
-	-	1	Pulmonary fibrosis and/or bone marrow failure, Telomere-related, 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.085
DANN	Benign	0.63
PhyloP100		-4.8
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: rs35033501; hg19: chr5-1253918;