rs746216837

Variant names:

• chr5-1293424-G-A
• rs746216837
• NM_198253.3:c.1462C>T

Your query was ambiguous. Multiple possible variants found:

• chr5-1293424-G-A
• chr5-1293424-G-T

Variant summary

Our verdict is Uncertain significance. The variant received 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. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L488V) has been classified as Uncertain significance.

• 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:2 B:1
• Conservation: PhyloP100: -0.228
• Publications: 0 publications found

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]

TERT Gene-Disease associations (from GenCC):

• pulmonary fibrosis and/or bone marrow failure, Telomere-related, 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• dyskeratosis congenita, autosomal dominant 2

  Inheritance: AR, AD, SD, Unknown Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Ambry Genetics, G2P, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), ClinGen, Laboratory for Molecular Medicine
• acute myeloid leukemia

  Inheritance: AD Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• dyskeratosis congenita

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Hoyeraal-Hreidarsson syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• melanoma, cutaneous malignant, susceptibility to, 9

  Inheritance: AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 benign, 15 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 VariationId is 436987.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TERT	NM_198253.3	c.1462C>T	p.Leu488Phe	missense_variant	Exon 2 of 16	ENST00000310581.10	NP_937983.2
TERT	NM_001193376.3	c.1462C>T	p.Leu488Phe	missense_variant	Exon 2 of 15		NP_001180305.1
TERT	NR_149162.3	n.1541C>T		non_coding_transcript_exon_variant	Exon 2 of 13
TERT	NR_149163.3	n.1541C>T		non_coding_transcript_exon_variant	Exon 2 of 13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TERT	ENST00000310581.10	c.1462C>T	p.Leu488Phe	missense_variant	Exon 2 of 16	1	NM_198253.3	ENSP00000309572.5
TERT	ENST00000334602.10	c.1462C>T	p.Leu488Phe	missense_variant	Exon 2 of 15	1		ENSP00000334346.6
TERT	ENST00000460137.6	n.1462C>T		non_coding_transcript_exon_variant	Exon 2 of 13	1		ENSP00000425003.1
TERT	ENST00000656021.1	n.1462C>T		non_coding_transcript_exon_variant	Exon 2 of 17			ENSP00000499759.1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD2 exomes AF: 0.00000805 AC: 2 AN: 248298 AF XY: 0.00000741

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 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

African (AFR) AF: 0.00 AC: 0 AN: 33474

American (AMR) AF: 0.00 AC: 0 AN: 44686

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26110

East Asian (EAS) AF: 0.00 AC: 0 AN: 39684

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86176

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52428

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111844

Other (OTH) AF: 0.00 AC: 0 AN: 60354

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:2 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1

Nov 30, 2016

Genetic Services Laboratory, University of Chicago

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Dyskeratosis congenita Uncertain:1

Aug 27, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.L488F variant (also known as c.1462C>T), located in coding exon 2 of the TERT gene, results from a C to T substitution at nucleotide position 1462. The leucine at codon 488 is replaced by phenylalanine, an amino acid with highly similar properties. This amino acid position is conserved. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear.

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

Feb 16, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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
PhyloP100		-0.23
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
Vest4		0.15
ClinPred		0.017	T
GERP RS		-4.0
Varity_R		0.082
gMVP		0.41
Mutation Taster		=80/20	polymorphism

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

Other links and lift over

dbSNP: rs746216837; hg19: chr5-1293539;