rs1554041299

chr5-1282488-C-Achr5-1282488-C-Gchr5-1282488-C-N

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2 PM5 PP3_Moderate PP5

The NM_198253.3(TERT):c.1710G>T(p.Lys570Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely risk allele (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K570?) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TERT NM_198253.3 missense
• Clinical Significance: Likely risk allele no assertion criteria provided P:1
• Conservation: PhyloP100: 0.912

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 Likely_pathogenic. Variant got 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr5-1282488-C-R is described in ClinVar as [Pathogenic]. Clinvar id is 39103.Status of the report is no_assertion_criteria_provided, 0 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.881
• PP5: Variant 5-1282488-C-A is Pathogenic according to our data. Variant chr5-1282488-C-A is described in ClinVar as [Likely_risk_allele]. Clinvar id is 1695955.Status of the report is no_assertion_criteria_provided, 0 stars. We mark this variant Likely_pathogenic, oryginal submission is: [Likely_risk_allele].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TERT	NM_198253.3	c.1710G>T	p.Lys570Asn	missense_variant	3/16	ENST00000310581.10
TERT	NM_001193376.3	c.1710G>T	p.Lys570Asn	missense_variant	3/15
TERT	NR_149162.3	n.1789G>T		non_coding_transcript_exon_variant	3/13
TERT	NR_149163.3	n.1789G>T		non_coding_transcript_exon_variant	3/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TERT	ENST00000310581.10	c.1710G>T	p.Lys570Asn	missense_variant	3/16	1	NM_198253.3	P2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely risk allele

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Pulmonary fibrosis Pathogenic:1

Likely risk allele, no assertion criteria provided

research

Garcia Pulmonary Genetics Research Laboratory, Columbia University Irving Medical Center

Jun 09, 2022

Leukocyte telomere length (by qPCR) less than 10th percentile age-adjusted -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Uncertain	0.095	D
BayesDel_noAF	Benign	-0.10
Cadd	Uncertain	24
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.90	D;.
Eigen	Uncertain	0.50
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Benign	0.86	D;D
M_CAP	Pathogenic	0.64	D
MetaRNN	Pathogenic	0.88	D;D
MetaSVM	Uncertain	0.70	D
MutationAssessor	Pathogenic	3.2	M;M
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.56	T
PROVEAN	Uncertain	-3.8	D;D
REVEL	Pathogenic	0.81
Sift	Uncertain	0.0020	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;D
Vest4		0.48
MutPred		0.80		Loss of methylation at K570 (P = 0.0059);Loss of methylation at K570 (P = 0.0059);
MVP		0.95
MPC		2.4
ClinPred		0.99	D
GERP RS		2.4
Varity_R		0.95
gMVP		0.97

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

Publications

LitVar

Other links and lift over

dbSNP: rs1554041299; hg19: chr5-1282603; COSMIC: COSV99719050;