rs199422295

chr5-1279376-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PP3_Strong

The NM_198253.3(TERT):c.2045G>A(p.Gly682Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as not provided (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G682R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: TERT NM_198253.3 missense
• Clinical Significance: not provided no classification provided O:1
• Conservation: PhyloP100: 1.69

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 6 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 11 uncertain in NM_198253.3
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.983

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TERT	NM_198253.3	c.2045G>A	p.Gly682Asp	missense_variant	5/16	ENST00000310581.10
TERT	NM_001193376.3	c.2045G>A	p.Gly682Asp	missense_variant	5/15
TERT	NR_149162.3	n.2124G>A		non_coding_transcript_exon_variant	5/13
TERT	NR_149163.3	n.2124G>A		non_coding_transcript_exon_variant	5/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TERT	ENST00000310581.10	c.2045G>A	p.Gly682Asp	missense_variant	5/16	1	NM_198253.3	P2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1413070 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 698768

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 0.00

GnomAD4 genome Cov.: 33

Alfa AF: 0.000106 Hom.: 0

ClinVar

Significance: not provided

Submissions summary: Other:1

Revision: no classification provided

Submissions by phenotype

Dyskeratosis congenita, autosomal dominant 1 Other:1

not provided, no classification provided

literature only

GeneReviews

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.76
BayesDel_addAF	Pathogenic	0.51	D
BayesDel_noAF	Pathogenic	0.49
Cadd	Benign	23
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.84	D;.
Eigen	Uncertain	0.36
Eigen_PC	Uncertain	0.26
FATHMM_MKL	Benign	0.52	D
LIST_S2	Uncertain	0.92	D;D
M_CAP	Pathogenic	0.94	D
MetaRNN	Pathogenic	0.98	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.6	M;M
MutationTaster	Benign	1.0	A;A;A;A
PrimateAI	Uncertain	0.74	T
PROVEAN	Pathogenic	-4.9	D;D
REVEL	Pathogenic	0.81
Sift	Pathogenic	0.0	D;D
Sift4G	Uncertain	0.0080	D;D
Polyphen		1.0	D;D
Vest4		0.73
MutPred		0.83		Loss of MoRF binding (P = 0.0549);Loss of MoRF binding (P = 0.0549);
MVP		0.99
MPC		2.5
ClinPred		0.99	D
GERP RS		4.7
Varity_R		0.83
gMVP		1.0

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: rs199422295; hg19: chr5-1279491;