rs587776370

Variant names:

• chr5-1260509-G-A
• rs199422305
• NM_198253.3:c.2935C>T

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_198253.3(TERT):​c.2935C>T​(p.Arg979Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,826 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R979Q) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: TERT NM_198253.3 missense
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:3 O:2
• Conservation: PhyloP100: 0.839
• Publications: 9 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: Pathogenic. The variant received 18 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 17 uncertain in NM_198253.3
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr5-1260508-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 506255.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.994
• PP5: Variant 5-1260509-G-A is Pathogenic according to our data. Variant chr5-1260509-G-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 39118.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TERT	NM_198253.3	c.2935C>T	p.Arg979Trp	missense_variant	Exon 12 of 16	ENST00000310581.10	NP_937983.2
TERT	NM_001193376.3	c.2746C>T	p.Arg916Trp	missense_variant	Exon 11 of 15		NP_001180305.1
TERT	NR_149162.3	n.2643C>T		non_coding_transcript_exon_variant	Exon 9 of 13
TERT	NR_149163.3	n.2607C>T		non_coding_transcript_exon_variant	Exon 9 of 13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TERT	ENST00000310581.10	c.2935C>T	p.Arg979Trp	missense_variant	Exon 12 of 16	1	NM_198253.3	ENSP00000309572.5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461826 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 727210

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53394

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000360 AC: 4 AN: 1111982

Other (OTH) AF: 0.00 AC: 0 AN: 60392

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:3 Other:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Oct 22, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 979 of the TERT protein (p.Arg979Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of idiopathic pulmonary fibrosis and/or dyskeratosis congenita (PMID: 15885610, 26360549; internal data). ClinVar contains an entry for this variant (Variation ID: 39118). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt TERT protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects TERT function (PMID: 12167716, 21602826, 23901009, 28154186). This variant disrupts the p.Arg979 amino acid residue in TERT. Other variant(s) that disrupt this residue have been observed in individuals with TERT-related conditions (internal data), which suggests that this may be a clinically significant amino acid residue. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

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

- -

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

May 02, 2024

Molecular Genetics, Royal Melbourne Hospital

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change in TERT is predicted to replace arginine with tryptophan at codon 979, p.(Arg979Trp). The arginine residue is moderately conserved (100 vertebrates, Multiz Alignments), and is located in the E-I motif of the Thumb domain (PMID: 28154186). There is a large physicochemical difference between arginine and tryptophan. The highest population minor allele frequency in the population database gnomAD v4.0 is 0.0005% (4/761,904 alleles) in the European (non-Finnish) population. This variant has been reported in at least seven probands with a phenotype consistent with a telomere-mediated disorder and segregated with disease in two families (PMID: 21602826, 26360549, 29891356, 33214205; ClinVar: RCV002509176.8; Royal Melbourne Hospital). At least one patient with this variant displayed lymphocyte telomere lengths less than the first percentile, which is consistent with a telomere biology disorder (PMID: 21602826). In vitro functional studies assessing the variant without appropriate controls demonstrated reduced to no effect on telomerase activity (PMID: 16990594, 21602826, 23901009, 28154186). Computational evidence is uninformative for the missense substitution (REVEL = 0.602). Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.6.1, this variant is classified as LIKELY PATHOGENIC. Following criteria are met: PS4_Moderate, PP1_Moderate, PM2_Supporting, PP4. -

Aplastic anemia Other:1

-

Radiation Cancer Biology Lab, University of Rajasthan Jaipur

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Dyskeratosis congenita, autosomal dominant 1 Other:1

-

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.060
CADD	Uncertain	24
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.93	D;.
Eigen	Uncertain	0.26
Eigen_PC	Benign	0.087
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Uncertain	0.96	D;D
M_CAP	Pathogenic	0.65	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Uncertain	0.035	D
MutationAssessor	Uncertain	2.6	M;.
PhyloP100		0.84
PrimateAI	Benign	0.36	T
PROVEAN	Pathogenic	-5.5	D;D
REVEL	Uncertain	0.60
Sift	Uncertain	0.0010	D;D
Sift4G	Pathogenic	0.0010	D;D
Polyphen		1.0	D;D
Vest4		0.80
MutPred		0.84		Loss of methylation at R979 (P = 0.0123);.;
MVP		0.89
MPC		2.3
ClinPred		0.98	D
GERP RS		1.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.45
gMVP		0.74
Mutation Taster		=29/71	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs199422305; hg19: chr5-1260624; COSMIC: COSV106097324;