rs1554042899

Variant names:

• chr5-1293836-CAG-C
• rs1554042899
• NM_198253.3:c.1048_1049delCT

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_198253.3(TERT):​c.1048_1049delCT​(p.Leu350GlufsTer188) variant causes a frameshift 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 Pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 34)
• Consequence: TERT NM_198253.3 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 2.84

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 Pathogenic. Variant got 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 5-1293836-CAG-C is Pathogenic according to our data. Variant chr5-1293836-CAG-C is described in ClinVar as [Pathogenic]. Clinvar id is 539192.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TERT	NM_198253.3	c.1048_1049delCT	p.Leu350GlufsTer188	frameshift_variant	Exon 2 of 16	ENST00000310581.10	NP_937983.2
TERT	NM_001193376.3	c.1048_1049delCT	p.Leu350GlufsTer188	frameshift_variant	Exon 2 of 15		NP_001180305.1
TERT	NR_149162.3	n.1127_1128delCT		non_coding_transcript_exon_variant	Exon 2 of 13
TERT	NR_149163.3	n.1127_1128delCT		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.1048_1049delCT	p.Leu350GlufsTer188	frameshift_variant	Exon 2 of 16	1	NM_198253.3	ENSP00000309572.5
TERT	ENST00000334602.10	c.1048_1049delCT	p.Leu350GlufsTer188	frameshift_variant	Exon 2 of 15	1		ENSP00000334346.6
TERT	ENST00000460137.6	n.1048_1049delCT		non_coding_transcript_exon_variant	Exon 2 of 13	1		ENSP00000425003.1
TERT	ENST00000656021.1	n.1048_1049delCT		non_coding_transcript_exon_variant	Exon 2 of 17			ENSP00000499759.1

Frequencies

GnomAD3 genomes Cov.: 34

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 34

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

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

Oct 03, 2017

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in TERT are known to be pathogenic (PMID: 16247010, 17460043). This variant has not been reported in the literature in individuals with TERT-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Leu350Glufs*188) in the TERT gene. It is expected to result in an absent or disrupted protein product. -

Pulmonary fibrosis Pathogenic:1

Jun 09, 2022

Garcia Pulmonary Genetics Research Laboratory, Columbia University Irving Medical Center

Significance: Likely risk allele

Review Status: no assertion criteria provided

Collection Method: research

Leukocyte telomere length (by qPCR) less than 10th percentile age-adjusted -

Computational scores

Source: dbNSFP v4.3

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: rs1554042899; hg19: chr5-1293951;