5-1279407-G-T

Variant names:

• chr5-1279407-G-T
• rs368430301
• NM_198253.3:c.2014C>A

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM1 PM2

The NM_198253.3(TERT):​c.2014C>A​(p.Arg672Ser) variant causes a missense 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R672H) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: TERT NM_198253.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 0.462
• 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: Uncertain_significance. The variant received 4 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 4 benign, 25 uncertain in NM_198253.3
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TERT	NM_198253.3	c.2014C>A	p.Arg672Ser	missense_variant	Exon 5 of 16	ENST00000310581.10	NP_937983.2
TERT	NM_001193376.3	c.2014C>A	p.Arg672Ser	missense_variant	Exon 5 of 15		NP_001180305.1
TERT	NR_149162.3	n.2093C>A		non_coding_transcript_exon_variant	Exon 5 of 13
TERT	NR_149163.3	n.2093C>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.2014C>A	p.Arg672Ser	missense_variant	Exon 5 of 16	1	NM_198253.3	ENSP00000309572.5

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1399994 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 691114

African (AFR) AF: 0.00 AC: 0 AN: 31736

American (AMR) AF: 0.00 AC: 0 AN: 36104

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25194

East Asian (EAS) AF: 0.00 AC: 0 AN: 36040

South Asian (SAS) AF: 0.00 AC: 0 AN: 79438

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47938

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4300

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1081298

Other (OTH) AF: 0.00 AC: 0 AN: 57946

GnomAD4 genome Cov.: 34

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Apr 25, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with serine, which is neutral and polar, at codon 672 of the TERT protein (p.Arg672Ser). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with TERT-related conditions. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt TERT protein function. 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. -

Dyskeratosis congenita Uncertain:1

Nov 10, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.R672S variant (also known as c.2014C>A), located in coding exon 5 of the TERT gene, results from a C to A substitution at nucleotide position 2014. The arginine at codon 672 is replaced by serine, an amino acid with dissimilar properties. This amino acid position is conserved. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this variant remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Uncertain	-0.010
CADD	Benign	10
DANN	Benign	0.95
DEOGEN2	Benign	0.38	T;.
Eigen	Benign	-0.38
Eigen_PC	Benign	-0.50
FATHMM_MKL	Benign	0.018	N
LIST_S2	Benign	0.80	T;T
M_CAP	Pathogenic	0.66	D
MetaRNN	Uncertain	0.44	T;T
MetaSVM	Uncertain	0.26	D
MutationAssessor	Uncertain	2.5	M;M
PhyloP100		0.46
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-1.1	N;N
REVEL	Uncertain	0.43
Sift	Benign	0.32	T;T
Sift4G	Benign	0.15	T;T
Polyphen		0.80	P;P
Vest4		0.32
MutPred		0.50		Gain of phosphorylation at R672 (P = 0.0313);Gain of phosphorylation at R672 (P = 0.0313);
MVP		0.87
MPC		1.4
ClinPred		0.55	D
GERP RS		3.8
Varity_R		0.097
gMVP		0.76
Mutation Taster		=32/68	disease causing

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: rs368430301; hg19: chr5-1279522;