rs797046041

Positions:

• chr5-1282578-G-C
• chr5-1282578-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP5_Moderate

The NM_198253.3(TERT):​c.1620C>G​(p.Ile540Met) 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 Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TERT NM_198253.3 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 1.01

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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 5-1282578-G-C is Pathogenic according to our data. Variant chr5-1282578-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 212399.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TERT	NM_198253.3	c.1620C>G	p.Ile540Met	missense_variant	3/16	ENST00000310581.10	NP_937983.2
TERT	NM_001193376.3	c.1620C>G	p.Ile540Met	missense_variant	3/15		NP_001180305.1
TERT	NR_149162.3	n.1699C>G		non_coding_transcript_exon_variant	3/13
TERT	NR_149163.3	n.1699C>G		non_coding_transcript_exon_variant	3/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TERT	ENST00000310581.10	c.1620C>G	p.Ile540Met	missense_variant	3/16	1	NM_198253.3	ENSP00000309572	P2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Acute myeloid leukemia Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Jul 28, 2015

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Uncertain	0.054	T
BayesDel_noAF	Benign	-0.16
CADD	Benign	19
DANN	Uncertain	0.97
DEOGEN2	Uncertain	0.53	D;.
Eigen	Uncertain	0.25
Eigen_PC	Benign	0.12
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.87	D;D
M_CAP	Pathogenic	0.42	D
MetaRNN	Uncertain	0.57	D;D
MetaSVM	Uncertain	0.40	D
MutationAssessor	Benign	2.0	M;M
MutationTaster	Benign	0.99	D;D;D;D
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-1.4	N;N
REVEL	Uncertain	0.55
Sift	Uncertain	0.0020	D;D
Sift4G	Pathogenic	0.0010	D;D
Polyphen		0.99	D;P
Vest4		0.33
MutPred		0.55		Gain of disorder (P = 0.0467);Gain of disorder (P = 0.0467);
MVP		0.86
MPC		2.2
ClinPred		0.70	D
GERP RS		3.8
Varity_R		0.64
gMVP		0.57

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: rs797046041; hg19: chr5-1282693;