rs199422272

Variant names:

• chr3-169764945-G-A
• rs199422272
• ENST00000602385.3:n.116C>T

Your query was ambiguous. Multiple possible variants found:

• chr3-169764945-G-A
• chr3-169764945-G-C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 3P and 1B. PM2 PP5 BP4

The ENST00000602385.3(TERC):​n.116C>T variant causes a non coding transcript exon change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TERC ENST00000602385.3 non_coding_transcript_exon
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4 U:1
• Conservation: PhyloP100: 3.90
• Publications: 3 publications found

Genes affected

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]

TERC Gene-Disease associations (from GenCC):

• dyskeratosis congenita, autosomal dominant 1

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• acute myeloid leukemia

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp

ENSG00000296372 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 3-169764945-G-A is Pathogenic according to our data. Variant chr3-169764945-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 7326.
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.14). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TERC	NR_001566.3	n.116C>T		non_coding_transcript_exon_variant	Exon 1 of 1	ENST00000602385.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TERC	ENST00000602385.3	n.116C>T		non_coding_transcript_exon_variant	Exon 1 of 1	6	NR_001566.3
ENSG00000296372	ENST00000738610.1	n.560G>A		non_coding_transcript_exon_variant	Exon 1 of 1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 0

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:4 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

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

Mar 26, 2020

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is not present in population databases (ExAC no frequency). 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. 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. This variant has been observed in individual(s) with aplastic anemia (PMID: 14630445). ClinVar contains an entry for this variant (Variation ID: 7326). This variant occurs in the TERC gene, which encodes an RNA molecule that does not result in a protein product.

May 10, 2012

GeneReviews

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: curation

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

Pulmonary fibrosis and/or bone marrow failure, Telomere-related, 2 Pathogenic:1

Nov 15, 2003

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

not provided Pathogenic:1

Nov 15, 2019

Genetic Services Laboratory, University of Chicago

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

DNA sequence analysis of the TERC gene demonstrated a sequence change, n.116C>T. This sequence change affects a highly conserved nucleotide located in a domain of the telomerase RNA that is known to be functional. This sequence change has not been described in population databases (gnomAD, ExAC). The n.116C>T change has been identified in individuals with aplastic anemia, telomeres shortening, and thrombocytopenia (PMID: 20022961, 14630445, 16670076). Functional studies revealed a partial loss of function in telomerase catalytic activation in the presence of this sequence change (PMID: 20022961).

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.14
CADD	Benign	22
DANN	Benign	0.96
PhyloP100		3.9

Splicing

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

Other links and lift over

dbSNP: rs199422272; hg19: chr3-169482733;