rs199422260

chr3-169765026-G-Achr3-169765026-G-Cchr3-169765026-G-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NR_001566.1(TERC):n.35C>T variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000144 in 765,134 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000015 (0 hom.)
• Consequence: TERC NR_001566.1 non_coding_transcript_exon
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts P:1 U:2
• Conservation: PhyloP100: -2.13

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 Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.56).
• BS2: High AC in GnomAdExome at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TERC	NR_001566.1	n.35C>T		non_coding_transcript_exon_variant	1/1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
Telomerase-vert	ENST00000363312.1	n.22C>T		non_coding_transcript_exon_variant	1/1
TERC	ENST00000602385.1	n.35C>T		non_coding_transcript_exon_variant	1/1

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152230 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000217 AC: 5 AN: 230684 Hom.: 0 AF XY: 0.0000314 AC XY: 4 AN XY: 127544

Gnomad AFR exome AF: 0.0000727

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000330

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000279

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000147 AC: 9 AN: 612904 Hom.: 0 Cov.: 0 AF XY: 0.0000179 AC XY: 6 AN XY: 334988

Gnomad4 AFR exome AF: 0.0000566

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000143

Gnomad4 FIN exome AF: 0.0000265

Gnomad4 NFE exome AF: 0.0000172

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152230 Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2 AN XY: 74374

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00

Alfa AF: 0.00000994 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Oct 03, 2023	This variant occurs in the TERC gene, which encodes an RNA molecule that does not result in a protein product. This variant is present in population databases (rs199422260, gnomAD 0.004%). This variant has been observed in individual(s) with hypoplastic myelodysplastic syndrome and dyskeratosis congenita (PMID: 18931339, 27622320). ClinVar contains an entry for this variant (Variation ID: 39292). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this variant affects TERC function (PMID: 18931339). 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). This variant is located in a region of TERC in which a significant number of disease causing variants have been reported (PMID: 15082312, 21844345, 21931702). These observations suggest that this may be a clinically significant region. 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. -
Pathogenic, no assertion criteria provided	curation	GeneReviews	May 10, 2012	- -

Pulmonary fibrosis and/or bone marrow failure, Telomere-related, 2;C4551974:Dyskeratosis congenita, autosomal dominant 1 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Dec 15, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.56
Cadd	Benign	2.7
Dann	Benign	0.86
RBP_binding_hub_radar		1.0
RBP_regulation_power_radar		3.6

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs199422260; hg19: chr3-169482814;