rs199422289

chr5-1294893-G-Achr5-1294893-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP5

The NM_198253.3(TERT):c.97C>T(p.Pro33Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000156 in 1,282,832 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. P33L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000016 (0 hom.)
• Consequence: TERT NM_198253.3 missense
• Clinical Significance: Likely risk allele no assertion criteria provided P:1 O:1
• Conservation: PhyloP100: -0.485

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.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 5-1294893-G-A is Pathogenic according to our data. Variant chr5-1294893-G-A is described in ClinVar as [Likely_risk_allele]. Clinvar id is 39127.Status of the report is no_assertion_criteria_provided, 0 stars. We mark this variant Likely_pathogenic, oryginal submissions are: {not_provided=1}. Variant chr5-1294893-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TERT	NM_198253.3	c.97C>T	p.Pro33Ser	missense_variant	1/16	ENST00000310581.10
TERT	NM_001193376.3	c.97C>T	p.Pro33Ser	missense_variant	1/15
TERT	NR_149162.3	n.176C>T		non_coding_transcript_exon_variant	1/13
TERT	NR_149163.3	n.176C>T		non_coding_transcript_exon_variant	1/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TERT	ENST00000310581.10	c.97C>T	p.Pro33Ser	missense_variant	1/16	1	NM_198253.3	P2
TERT	ENST00000334602.10	c.97C>T	p.Pro33Ser	missense_variant	1/15	1		A2
TERT	ENST00000460137.6	c.97C>T	p.Pro33Ser	missense_variant, NMD_transcript_variant	1/13	1
TERT	ENST00000656021.1	c.97C>T	p.Pro33Ser	missense_variant, NMD_transcript_variant	1/17

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 0.00000156 AC: 2 AN: 1282832 Hom.: 0 Cov.: 34 AF XY: 0.00000158 AC XY: 1 AN XY: 630968

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.0000459

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.70e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 34

ClinVar

Significance: Likely risk allele

Submissions summary: Pathogenic:1 Other: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 -

Interstitial lung disease 2 Other:1

not provided, no classification provided

literature only

GeneReviews

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.070
Cadd	Benign	16
Dann	Benign	0.85
DEOGEN2	Uncertain	0.54	D;.
Eigen	Benign	-0.48
Eigen_PC	Benign	-0.50
FATHMM_MKL	Benign	0.025	N
LIST_S2	Benign	0.81	T;T
M_CAP	Pathogenic	0.97	D
MetaRNN	Uncertain	0.55	D;D
MetaSVM	Uncertain	-0.12	T
MutationAssessor	Uncertain	2.3	M;M
MutationTaster	Benign	0.26	A;A;A;A
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	-1.6	N;N
REVEL	Uncertain	0.61
Sift	Benign	0.45	T;T
Sift4G	Benign	0.34	T;T
Polyphen		0.27	B;B
Vest4		0.28
MutPred		0.43		Gain of catalytic residue at P33 (P = 0.0859);Gain of catalytic residue at P33 (P = 0.0859);
MVP		0.95
MPC		1.1
ClinPred		0.15	T
GERP RS		3.0
Varity_R		0.095
gMVP		0.47

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs199422289; hg19: chr5-1295008;