5-1279414-C-T

Variant names:

• chr5-1279414-C-T
• rs1060504788
• NM_198253.3:c.2007G>A

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 2P and 13B. PM2 BP4_Strong BP6_Very_Strong BP7

The NM_198253.3(TERT):​c.2007G>A​(p.Arg669Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000286 in 1,399,880 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 Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. R669R) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000029 (0 hom.)
• Consequence: TERT NM_198253.3 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -2.18
• Publications: 0 publications found

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]

TERT Gene-Disease associations (from GenCC):

• pulmonary fibrosis and/or bone marrow failure, Telomere-related, 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• dyskeratosis congenita, autosomal dominant 2

  Inheritance: AR, AD, SD, Unknown Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Ambry Genetics, G2P, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), ClinGen, Laboratory for Molecular Medicine
• acute myeloid leukemia

  Inheritance: AD Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• dyskeratosis congenita

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Hoyeraal-Hreidarsson syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• melanoma, cutaneous malignant, susceptibility to, 9

  Inheritance: AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -11 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.76).
• BP6: Variant 5-1279414-C-T is Benign according to our data. Variant chr5-1279414-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 1670589.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.18 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TERT	NM_198253.3	c.2007G>A	p.Arg669Arg	synonymous_variant	Exon 5 of 16	ENST00000310581.10	NP_937983.2
TERT	NM_001193376.3	c.2007G>A	p.Arg669Arg	synonymous_variant	Exon 5 of 15		NP_001180305.1
TERT	NR_149162.3	n.2086G>A		non_coding_transcript_exon_variant	Exon 5 of 13
TERT	NR_149163.3	n.2086G>A		non_coding_transcript_exon_variant	Exon 5 of 13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TERT	ENST00000310581.10	c.2007G>A	p.Arg669Arg	synonymous_variant	Exon 5 of 16	1	NM_198253.3	ENSP00000309572.5

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 0.00000286 AC: 4 AN: 1399880 Hom.: 0 Cov.: 33 AF XY: 0.00000434 AC XY: 3 AN XY: 690896

African (AFR) AF: 0.00 AC: 0 AN: 31726

American (AMR) AF: 0.00 AC: 0 AN: 36048

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25212

East Asian (EAS) AF: 0.00 AC: 0 AN: 36014

South Asian (SAS) AF: 0.0000504 AC: 4 AN: 79398

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48060

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4364

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1081106

Other (OTH) AF: 0.00 AC: 0 AN: 57952

GnomAD4 genome Cov.: 34

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Acute myeloid leukemia;C3151443:Dyskeratosis congenita, autosomal dominant 2;C3553617:Pulmonary fibrosis and/or bone marrow failure, Telomere-related, 1;C3554574:Melanoma, cutaneous malignant, susceptibility to, 9 Benign:1

-

Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant has not been reported in the literature and is not present in large control databases. This variant is present in ClinVar (Variation ID: 1670589). This is a silent variant and does not change the amino acid and is not predicted to impact splicing; additionally, this nucleotide position is not well-conserved evolutionarily, reducing the probability that this variant is disease-causing. In summary, data on this variant suggests that this variant does not cause disease but requires further evidence. Therefore, this variant is classified as likely benign -

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

May 19, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dyskeratosis congenita Benign:1

Sep 14, 2020

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
CADD	Benign	1.4
DANN	Benign	0.49
PhyloP100		-2.2
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs1060504788; hg19: chr5-1279529; COSMIC: COSV57239611;