rs199422263

Positions:

• chr3-169765003-CAGTT-C

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2 PP5_Very_Strong

The NR_001566.1(TERC):​n.54_57del variant causes a non coding transcript exon 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 (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TERC NR_001566.1 non_coding_transcript_exon
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 0.588

Genes affected

Telomerase-vert (HGNC:):

TERC (HGNC:11727): (telomerase RNA component) 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, and an RNA component, encoded by this gene, that 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. Mutations in this gene cause autosomal dominant dyskeratosis congenita, and may also be associated with some cases of aplastic anemia. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Pathogenic. Variant got 10 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 3-169765003-CAGTT-C is Pathogenic according to our data. Variant chr3-169765003-CAGTT-C is described in ClinVar as [Pathogenic]. Clinvar id is 30265.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-169765003-CAGTT-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TERC	NR_001566.1	n.54_57del		non_coding_transcript_exon_variant	1/1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
Telomerase-vert	ENST00000363312.1	n.41_44del		non_coding_transcript_exon_variant	1/1
TERC	ENST00000602385.1	n.54_57del		non_coding_transcript_exon_variant	1/1

Frequencies

GnomAD3 genomes Cov.: 32

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

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Dyskeratosis congenita, autosomal dominant 1 Pathogenic:3

Pathogenic, no assertion criteria provided	curation	GeneReviews	May 10, 2012	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 03, 2020	This variant occurs in the TERC gene, which encodes an RNA molecule that does not result in a protein product. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with dyskeratosis congenita (DC) and with clinical features of DC (PMID: 22341970, 16332973, Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 30265). This variant is located within the template/pseudoknot domain of the TERC RNA component, which is required for RNA or RNP stability (PMID: 15082312, 21844345). Functional studies testing the effect of this variant on TERC secondary structure or function have not been reported. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Mar 09, 2012	- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Mayo Clinic Laboratories, Mayo Clinic

Feb 24, 2023

PP4, PM1, PM2_supporting, PS3, PS4_moderate -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs199422263; hg19: chr3-169482791;