chr3-169763862-ATCCTAAGGAATTGAAGGTATGGATTTGGGACGGAATTACCTTGTCGTGATAAGTGGGCAGAATGGCCTGTTTGTTTCTTTCAACCTAGTGGGCCATTAGCTTATTTTCTTAAAGGAAATCAGAGCCAATTCTTGTGGGAGACTGCCGGCTGGGAGGGTTGGGGGTGGGGGGTGTGGAATAAATTTCTTTTCCGTCTTTCATTATGCCTAGTGTTCCGTTATTGGAACGCTAAGCTTGTGGGGGTTATATCCTACTGCTCAAGGTCATCGCCAAGGTCTAATTTTTCAAAAAAGAAACTTCTAACCTCTGGCATAAACCGATGACCATTAAAGGAACACAATTTCCAATGTTCATTTAGATCTTCTAATTAAATATTCATTAAATGTTAAATGATCTCTCAAAAAAAAATGACTGTTCTCCCACACCCCGTTGAGGGGACTGGTCGAGATCTACCTTGGGAGAAGCAAAAACCTCAACAAAATCTGCAGAGCAGGAACTAAGTTGTAATACAACCATAAAAGGCAACAAAAAGCGGAAGACGGGAGAACCCACGCAGGAACGGCTCCAGGCAACCCCGGCTCACTGCCCATTCATTTTGGCCGACTTTGGAGGTGCCTTCACGTCTCCTGCCAATTTGCAGCACACTGGCCCAGTCAGTCAGGTTTGGGGGTTCACAAGCCCCCATTGCCGGCGAGGGGTGACGGATGCGCACGATCGGCGTTCCCCCCACCAACAGGAAAGCGAACTGCATGTGTGAGCCGAGTCCTGGGTGCACGTCCCACAGCTCAGGGAATCGCGCCGCGCGCGGGGACTCGCTCCGT-A

Position:

• chr3-169763862-ATCCTAAGGAATTGAAGGTATGGATTTGGGACGGAATTACCTTGTCGTGATAAGTGGGCAGAATGGCCTGTTTGTTTCTTTCAACCTAGTGGGCCATTAGCTTATTTTCTTAAAGGAAATCAGAGCCAATTCTTGTGGGAGACTGCCGGCTGGGAGGGTTGGGGGTGGGGGGTGTGGAATAAATTTCTTTTCCGTCTTTCATTATGCCTAGTGTTCCGTTATTGGAACGCTAAGCTTGTGGGGGTTATATCCTACTGCTCAAGGTCATCGCCAAGGTCTAATTTTTCAAAAAAGAAACTTCTAACCTCTGGCATAAACCGATGACCATTAAAGGAACACAATTTCCAATGTTCATTTAGATCTTCTAATTAAATATTCATTAAATGTTAAATGATCTCTCAAAAAAAAATGACTGTTCTCCCACACCCCGTTGAGGGGACTGGTCGAGATCTACCTTGGGAGAAGCAAAAACCTCAACAAAATCTGCAGAGCAGGAACTAAGTTGTAATACAACCATAAAAGGCAACAAAAAGCGGAAGACGGGAGAACCCACGCAGGAACGGCTCCAGGCAACCCCGGCTCACTGCCCATTCATTTTGGCCGACTTTGGAGGTGCCTTCACGTCTCCTGCCAATTTGCAGCACACTGGCCCAGTCAGTCAGGTTTGGGGGTTCACAAGCCCCCATTGCCGGCGAGGGGTGACGGATGCGCACGATCGGCGTTCCCCCCACCAACAGGAAAGCGAACTGCATGTGTGAGCCGAGTCCTGGGTGCACGTCCCACAGCTCAGGGAATCGCGCCGCGCGCGGGGACTCGCTCCGT-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NR_001566.3(TERC):​n.378_*747del variant causes a splice region, 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 Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TERC NR_001566.3 splice_region, non_coding_transcript_exon
• Clinical Significance: Uncertain significance criteria provided, single submitter P:2 U:1
• Conservation: PhyloP100: 0.617

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TERC	NR_001566.3	n.378_*747del		splice_region_variant, non_coding_transcript_exon_variant	1/1
TERC	NR_001566.3	n.378_*747del		downstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
Telomerase-vert	ENST00000363312.1	n.365_*747del		splice_region_variant, non_coding_transcript_exon_variant	1/1	6
TERC	ENST00000602385.1	n.378_*657del		splice_region_variant, non_coding_transcript_exon_variant	1/1	6
Telomerase-vert	ENST00000363312.1	n.365_*747del		downstream_gene_variant		6
TERC	ENST00000602385.1	n.378_*657del		downstream_gene_variant		6

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: Uncertain significance

Submissions summary: Pathogenic:2 Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Dyskeratosis congenita, autosomal dominant 1 Pathogenic:2 Uncertain:1

Pathogenic, no assertion criteria provided	curation	GeneReviews	May 10, 2012	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Sep 27, 2001	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jul 11, 2023	This variant is located within the BoxH/ACA scaRNA domain of the TERC RNA component, which is required for telomerase activity (PMID: 21844345). 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 (gnomAD no frequency). This variant has been observed in individual(s) with dyskeratosis congenita (Invitae). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

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: rs1553915517; hg19: chr3-169481650;