rs544215765

chr5-1294797-G-Cchr5-1294797-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM1 PM2 BP4

The NM_198253.3(TERT):c.193C>G(p.Pro65Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000984 in 1,524,376 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P65L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000066 (0 hom., cov: 34)
  • Exomes 𝑓: 0.0000036 (0 hom.)
• Consequence: TERT NM_198253.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:4 B:1
• Conservation: PhyloP100: 0.882

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 Uncertain_significance. Variant got 3 ACMG points.

• PM1: In a region_of_interest GQ motif (size 139) in uniprot entity TERT_HUMAN there are 20 pathogenic changes around while only 7 benign (74%) in NM_198253.3
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.26552075).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TERT	NM_198253.3	c.193C>G	p.Pro65Ala	missense_variant	1/16	ENST00000310581.10
TERT	NM_001193376.3	c.193C>G	p.Pro65Ala	missense_variant	1/15
TERT	NR_149162.3	n.272C>G		non_coding_transcript_exon_variant	1/13
TERT	NR_149163.3	n.272C>G		non_coding_transcript_exon_variant	1/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TERT	ENST00000310581.10	c.193C>G	p.Pro65Ala	missense_variant	1/16	1	NM_198253.3	P2
TERT	ENST00000334602.10	c.193C>G	p.Pro65Ala	missense_variant	1/15	1		A2
TERT	ENST00000460137.6	c.193C>G	p.Pro65Ala	missense_variant, NMD_transcript_variant	1/13	1
TERT	ENST00000656021.1	c.193C>G	p.Pro65Ala	missense_variant, NMD_transcript_variant	1/17

Frequencies

GnomAD3 genomes AF: 0.0000592 AC: 9 AN: 152134 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.000193

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000167 AC: 2 AN: 119432 Hom.: 0 AF XY: 0.0000151 AC XY: 1 AN XY: 66312

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000858

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000364 AC: 5 AN: 1372134 Hom.: 0 Cov.: 35 AF XY: 0.00000591 AC XY: 4 AN XY: 677132

Gnomad4 AFR exome AF: 0.0000678

Gnomad4 AMR exome AF: 0.0000572

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000175

GnomAD4 genome AF: 0.0000657 AC: 10 AN: 152242 Hom.: 0 Cov.: 34 AF XY: 0.0000806 AC XY: 6 AN XY: 74432

Gnomad4 AFR AF: 0.000216

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.000113

ExAC AF: 0.0000119 AC: 1

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:4 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Dyskeratosis congenita, autosomal dominant 2 Pathogenic:1 Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Oct 11, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	Feb 11, 2022	ACMG classification criteria: PS3 supporting, PS4 supporting, PP2 supporting, BP4 supporting -
Likely pathogenic, criteria provided, single submitter	clinical testing	Johns Hopkins Genomics, Johns Hopkins University	Jul 20, 2020	This TERT variant has been reported in patients presenting with cirrhosis and acute myeloid leukemia with aplastic anemia. Functional studies showed that this variant significantly reduces telomerase activity compared to the wildtype. TERT c.193C>G is located in the RNA-interaction domain within the N-terminal extension region. This variant (rs544215765) has a ClinVar entry, and is shown rare (<0.1%) in a large population dataset (gnomAD: 3/150704 total alleles; 0.002%; no homozygotes), however this frequency estimate may not be reliable due to low coverage at this position in gnomAD exomes. We consider this variant to be likely pathogenic. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Nov 03, 2023

Published functional studies are conflicting: some demonstrate reduced or absent telomerase activity and reduced cell growth compared to wildtype, while others failed to show significant reductions in telomerase activity and processivity (PMID: 19147845, 21520174, 23901009); Reported in the germline of individuals with aplastic anemia, myelodysplastic syndrome, and/or liver cirrhosis (PMID: 21520174, 30523342, 35969835); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 30995915, 19796246, 19636400, 23901009, 19147845, 21520174, 23716176, 35969835, 30523342) -

Dyskeratosis congenita Uncertain:1

Uncertain significance, criteria provided, single submitter

curation

Sema4, Sema4

Dec 20, 2021

- -

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

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Nov 27, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.089	T
BayesDel_noAF	Benign	-0.24
Cadd	Benign	13
Dann	Benign	0.93
DEOGEN2	Uncertain	0.46	T;.
Eigen	Benign	-0.40
Eigen_PC	Benign	-0.39
FATHMM_MKL	Benign	0.036	N
LIST_S2	Benign	0.68	T;T
M_CAP	Pathogenic	0.98	D
MetaRNN	Benign	0.27	T;T
MetaSVM	Uncertain	-0.091	T
MutationAssessor	Uncertain	2.4	M;M
MutationTaster	Benign	0.94	N;N;N;N
PrimateAI	Pathogenic	0.85	D
PROVEAN	Benign	-1.8	N;N
REVEL	Uncertain	0.31
Sift	Benign	0.26	T;T
Sift4G	Benign	0.083	T;T
Polyphen		0.056	B;B
Vest4		0.16
MutPred		0.52		Loss of glycosylation at P65 (P = 0.0085);Loss of glycosylation at P65 (P = 0.0085);
MVP		0.73
MPC		1.1
ClinPred		0.089	T
GERP RS		3.1
Varity_R		0.087
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: rs544215765; hg19: chr5-1294912;