rs754359147

Positions:

• chr5-1294184-C-G
• chr5-1294184-C-T

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM2 BP4_Moderate BP6

The NM_198253.3(TERT):​c.702G>C​(p.Leu234Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000253 in 1,582,574 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. L234L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 34)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: TERT NM_198253.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: 0.147

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]

ACMG classification

Verdict is Likely_benign. Variant got -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.12500209).
• BP6: Variant 5-1294184-C-G is Benign according to our data. Variant chr5-1294184-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 574022.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Likely_benign=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TERT	NM_198253.3	c.702G>C	p.Leu234Phe	missense_variant	2/16	ENST00000310581.10
TERT	NM_001193376.3	c.702G>C	p.Leu234Phe	missense_variant	2/15
TERT	NR_149162.3	n.781G>C		non_coding_transcript_exon_variant	2/13
TERT	NR_149163.3	n.781G>C		non_coding_transcript_exon_variant	2/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TERT	ENST00000310581.10	c.702G>C	p.Leu234Phe	missense_variant	2/16	1	NM_198253.3	P2
TERT	ENST00000334602.10	c.702G>C	p.Leu234Phe	missense_variant	2/15	1		A2
TERT	ENST00000460137.6	c.702G>C	p.Leu234Phe	missense_variant, NMD_transcript_variant	2/13	1
TERT	ENST00000656021.1	c.702G>C	p.Leu234Phe	missense_variant, NMD_transcript_variant	2/17

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152254 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

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: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000105 AC: 2 AN: 191010 Hom.: 0 AF XY: 0.00000939 AC XY: 1 AN XY: 106472

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000625

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000210 AC: 3 AN: 1430320 Hom.: 0 Cov.: 35 AF XY: 0.00000282 AC XY: 2 AN XY: 710106

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000698

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152254 Hom.: 0 Cov.: 34 AF XY: 0.0000134 AC XY: 1 AN XY: 74382

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000756

ExAC AF: 0.00000858 AC: 1

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Dyskeratosis congenita Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Mar 16, 2022	The p.L234F variant (also known as c.702G>C), located in coding exon 2 of the TERT gene, results from a G to C substitution at nucleotide position 702. The leucine at codon 234 is replaced by phenylalanine, an amino acid with highly similar properties. This amino acid position is conserved. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
Uncertain significance, criteria provided, single submitter	clinical testing	St. Jude Molecular Pathology, St. Jude Children's Research Hospital	Aug 19, 2021	The TERT c.702G>C (p.Leu234Phe) missense change has a maximum subpopulation frequency of 0.0063% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/variant/5-1294299-C-G). This variant occurs in a gene where missense variants are more likely to be damaging based on methods described by Lek et al. (PP2; PMID: 27535533). Six of seven in silico tools predict a benign effect of this variant on protein function (BP4), but to our knowledge these predictions have not been confirmed by functional assays. To our knowledge, this variant has not been reported in individuals with clinical features of dyskeratosis congenita. In summary, this variant meets criteria to be classified as of uncertain significance based on the ACMG/AMP criteria: PP2, BP4. -

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

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Nov 11, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.087
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	3.0
DANN	Benign	0.63
DEOGEN2	Benign	0.37	T;.
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.10	N
LIST_S2	Benign	0.70	T;T
M_CAP	Pathogenic	0.50	D
MetaRNN	Benign	0.13	T;T
MetaSVM	Uncertain	0.083	D
MutationAssessor	Benign	1.6	L;L
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	-0.90	N;N
REVEL	Uncertain	0.31
Sift	Benign	0.72	T;T
Sift4G	Benign	0.75	T;T
Polyphen		0.56	P;P
Vest4		0.13
MutPred		0.41		Loss of catalytic residue at L234 (P = 0.0631);Loss of catalytic residue at L234 (P = 0.0631);
MVP		0.79
MPC		1.3
ClinPred		0.074	T
GERP RS		-2.7
Varity_R		0.20
gMVP		0.40

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

Publications

LitVar

Other links and lift over

dbSNP: rs754359147; hg19: chr5-1294299;