rs144756946

chr5-1293748-G-Achr5-1293748-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_198253.3(TERT):c.1138C>T(p.Pro380Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000184 in 1,562,232 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P380T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00041 (1 hom., cov: 34)
  • Exomes 𝑓: 0.00016 (2 hom.)
• Consequence: TERT NM_198253.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.240

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0077765286).
• BP6: Variant 5-1293748-G-A is Benign according to our data. Variant chr5-1293748-G-A is described in ClinVar as [Benign]. Clinvar id is 242211.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-1293748-G-A is described in Lovd as [Likely_benign]. Variant chr5-1293748-G-A is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000407 (62/152366) while in subpopulation EAS AF= 0.00946 (49/5182). AF 95% confidence interval is 0.00735. There are 1 homozygotes in gnomad4. There are 37 alleles in male gnomad4 subpopulation. Median coverage is 34. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome at 2 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TERT	NM_198253.3	c.1138C>T	p.Pro380Ser	missense_variant	2/16	ENST00000310581.10
TERT	NM_001193376.3	c.1138C>T	p.Pro380Ser	missense_variant	2/15
TERT	NR_149162.3	n.1217C>T		non_coding_transcript_exon_variant	2/13
TERT	NR_149163.3	n.1217C>T		non_coding_transcript_exon_variant	2/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TERT	ENST00000310581.10	c.1138C>T	p.Pro380Ser	missense_variant	2/16	1	NM_198253.3	P2
TERT	ENST00000334602.10	c.1138C>T	p.Pro380Ser	missense_variant	2/15	1		A2
TERT	ENST00000460137.6	c.1138C>T	p.Pro380Ser	missense_variant, NMD_transcript_variant	2/13	1
TERT	ENST00000656021.1	c.1138C>T	p.Pro380Ser	missense_variant, NMD_transcript_variant	2/17

Frequencies

GnomAD3 genomes AF: 0.000401 AC: 61 AN: 152248 Hom.: 1 Cov.: 34

Gnomad AFR AF: 0.0000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00924

Gnomad SAS AF: 0.00227

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000808 AC: 135 AN: 167074 Hom.: 2 AF XY: 0.000865 AC XY: 77 AN XY: 89020

Gnomad AFR exome AF: 0.000105

Gnomad AMR exome AF: 0.0000393

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00997

Gnomad SAS exome AF: 0.000255

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000149

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000160 AC: 226 AN: 1409866 Hom.: 2 Cov.: 32 AF XY: 0.000191 AC XY: 133 AN XY: 696318

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000273

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00379

Gnomad4 SAS exome AF: 0.000537

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000184

Gnomad4 OTH exome AF: 0.000667

GnomAD4 genome AF: 0.000407 AC: 62 AN: 152366 Hom.: 1 Cov.: 34 AF XY: 0.000497 AC XY: 37 AN XY: 74506

Gnomad4 AFR AF: 0.0000481

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00946

Gnomad4 SAS AF: 0.00228

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000228 Hom.: 0

Bravo AF: 0.000227

ExAC AF: 0.000555 AC: 63

Asia WGS AF: 0.00520 AC: 18 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2022	TERT: BS1, BS2 -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Aug 11, 2021

- -

Interstitial lung disease 2 Benign:1

Benign, criteria provided, single submitter

clinical testing

Mendelics

May 28, 2019

- -

Idiopathic Pulmonary Fibrosis;C3151443:Dyskeratosis congenita, autosomal dominant 2 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

Hereditary cancer-predisposing syndrome;C0265965:Dyskeratosis congenita Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 23, 2018

This alteration is classified as benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Dyskeratosis congenita Benign:1

Benign, criteria provided, single submitter

curation

Sema4, Sema4

Mar 26, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Uncertain	0.060
Cadd	Benign	11
Dann	Benign	0.90
DEOGEN2	Benign	0.33	T;.
Eigen	Benign	-0.98
Eigen_PC	Benign	-0.96
FATHMM_MKL	Benign	0.19	N
LIST_S2	Benign	0.74	T;T
MetaRNN	Benign	0.0078	T;T
MetaSVM	Uncertain	-0.19	T
MutationAssessor	Benign	0.90	L;L
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	0.20	N;N
REVEL	Uncertain	0.55
Sift	Benign	0.061	T;T
Sift4G	Benign	0.15	T;T
Polyphen		0.010	B;B
Vest4		0.53
MVP		0.97
MPC		1.1
ClinPred		0.0063	T
GERP RS		1.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.045
gMVP		0.42

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

Publications

LitVar

Other links and lift over

dbSNP: rs144756946; hg19: chr5-1293863;