rs746216837

chr5-1293424-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 4P and 3B. PM1 PM2 BP4_Moderate BP6

The NM_198253.3(TERT):c.1462C>T(p.Leu488Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,524 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: TERT NM_198253.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: -0.228

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 1 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 8 uncertain in NM_198253.3
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.0847826).
• BP6: Variant 5-1293424-G-A is Benign according to our data. Variant chr5-1293424-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 436987.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TERT	NM_198253.3	c.1462C>T	p.Leu488Phe	missense_variant	2/16	ENST00000310581.10
TERT	NM_001193376.3	c.1462C>T	p.Leu488Phe	missense_variant	2/15
TERT	NR_149162.3	n.1541C>T		non_coding_transcript_exon_variant	2/13
TERT	NR_149163.3	n.1541C>T		non_coding_transcript_exon_variant	2/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TERT	ENST00000310581.10	c.1462C>T	p.Leu488Phe	missense_variant	2/16	1	NM_198253.3	P2
TERT	ENST00000334602.10	c.1462C>T	p.Leu488Phe	missense_variant	2/15	1		A2
TERT	ENST00000460137.6	c.1462C>T	p.Leu488Phe	missense_variant, NMD_transcript_variant	2/13	1
TERT	ENST00000656021.1	c.1462C>T	p.Leu488Phe	missense_variant, NMD_transcript_variant	2/17

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD3 exomes AF: 0.00000805 AC: 2 AN: 248298 Hom.: 0 AF XY: 0.00000741 AC XY: 1 AN XY: 134888

Gnomad AFR exome AF: 0.0000628

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000328

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460524 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 726558

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: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 34

Alfa AF: 0.0000329 Hom.: 0

Bravo AF: 0.0000113

ExAC AF: 0.00000825 AC: 1

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Nov 30, 2016

- -

Idiopathic Pulmonary Fibrosis;C3151443:Dyskeratosis congenita, autosomal dominant 2 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Feb 16, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.35
Cadd	Benign	1.4
Dann	Benign	0.11
DEOGEN2	Benign	0.36	T;.
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.057	N
LIST_S2	Benign	0.70	T;T
M_CAP	Uncertain	0.20	D
MetaRNN	Benign	0.085	T;T
MetaSVM	Benign	-0.78	T
MutationAssessor	Benign	0.66	N;N
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-0.21	N;N
REVEL	Benign	0.17
Sift	Benign	1.0	T;T
Sift4G	Benign	0.80	T;T
Polyphen		0.18	B;B
Vest4		0.15
MVP		0.73
MPC		1.4
ClinPred		0.017	T
GERP RS		-4.0
Varity_R		0.082
gMVP		0.41

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

LitVar

Other links and lift over

dbSNP: rs746216837; hg19: chr5-1293539;