rs387907248

Positions:

• chr5-1294378-C-G
• chr5-1294378-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PM5

The NM_198253.3(TERT):​c.508G>C​(p.Val170Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V170M) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 34)
• Consequence: TERT NM_198253.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.708

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 region_of_interest RNA-interacting domain 1 (size 229) in uniprot entity TERT_HUMAN there are 10 pathogenic changes around while only 3 benign (77%) in NM_198253.3
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr5-1294378-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TERT	NM_198253.3	c.508G>C	p.Val170Leu	missense_variant	2/16	ENST00000310581.10	NP_937983.2
TERT	NM_001193376.3	c.508G>C	p.Val170Leu	missense_variant	2/15		NP_001180305.1
TERT	NR_149162.3	n.587G>C		non_coding_transcript_exon_variant	2/13
TERT	NR_149163.3	n.587G>C		non_coding_transcript_exon_variant	2/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TERT	ENST00000310581.10	c.508G>C	p.Val170Leu	missense_variant	2/16	1	NM_198253.3	ENSP00000309572	P2
TERT	ENST00000334602.10	c.508G>C	p.Val170Leu	missense_variant	2/15	1		ENSP00000334346	A2
TERT	ENST00000460137.6	c.508G>C	p.Val170Leu	missense_variant, NMD_transcript_variant	2/13	1		ENSP00000425003
TERT	ENST00000656021.1	c.508G>C	p.Val170Leu	missense_variant, NMD_transcript_variant	2/17			ENSP00000499759

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 34

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

May 11, 2021

Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 30523342, 29463756) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.34
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.020
CADD	Benign	19
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.42	T;.
Eigen	Benign	0.13
Eigen_PC	Benign	0.12
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Uncertain	0.90	D;D
M_CAP	Pathogenic	0.66	D
MetaRNN	Uncertain	0.52	D;D
MetaSVM	Uncertain	0.74	D
MutationAssessor	Benign	2.0	M;M
MutationTaster	Benign	0.97	D;D;D;D
PrimateAI	Pathogenic	0.88	D
PROVEAN	Benign	-1.6	N;N
REVEL	Uncertain	0.62
Sift	Benign	0.11	T;T
Sift4G	Benign	0.25	T;D
Polyphen		0.65	P;P
Vest4		0.40
MutPred		0.29		Gain of glycosylation at P173 (P = 0.1729);Gain of glycosylation at P173 (P = 0.1729);
MVP		0.88
MPC		2.0
ClinPred		0.68	D
GERP RS		2.4
Varity_R		0.19
gMVP		0.93

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr5-1294493;