5-1294135-C-T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP6

The NM_198253.3(TERT):c.751G>A(p.Val251Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000154 in 1,429,202 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V251F) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.000015 (0 hom.)
• Consequence: TERT NM_198253.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: -2.39

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 -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.04268688).
• BP6: Variant 5-1294135-C-T is Benign according to our data. Variant chr5-1294135-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 539220.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TERT	NM_198253.3	c.751G>A	p.Val251Ile	missense_variant	2/16	ENST00000310581.10
TERT	NM_001193376.3	c.751G>A	p.Val251Ile	missense_variant	2/15
TERT	NR_149162.3	n.830G>A		non_coding_transcript_exon_variant	2/13
TERT	NR_149163.3	n.830G>A		non_coding_transcript_exon_variant	2/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TERT	ENST00000310581.10	c.751G>A	p.Val251Ile	missense_variant	2/16	1	NM_198253.3	P2
TERT	ENST00000334602.10	c.751G>A	p.Val251Ile	missense_variant	2/15	1		A2
TERT	ENST00000460137.6	c.751G>A	p.Val251Ile	missense_variant, NMD_transcript_variant	2/13	1
TERT	ENST00000656021.1	c.751G>A	p.Val251Ile	missense_variant, NMD_transcript_variant	2/17

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD3 exomes AF: 0.0000325 AC: 6 AN: 184778 Hom.: 0 AF XY: 0.0000196 AC XY: 2 AN XY: 102168

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000352

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000131

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000154 AC: 22 AN: 1429202 Hom.: 0 Cov.: 35 AF XY: 0.0000141 AC XY: 10 AN XY: 709264

Gnomad4 AFR exome AF: 0.0000306

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000186

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000109

Gnomad4 OTH exome AF: 0.0000338

GnomAD4 genome Cov.: 34

Bravo AF: 0.0000113

ExAC AF: 0.0000169 AC: 2

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Mar 16, 2023

In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

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

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 02, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Benign	-0.38
Cadd	Benign	0.95
Dann	Benign	0.83
DEOGEN2	Benign	0.33	T;.
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.032	N
LIST_S2	Benign	0.61	T;T
M_CAP	Pathogenic	0.29	D
MetaRNN	Benign	0.043	T;T
MetaSVM	Uncertain	-0.041	T
MutationAssessor	Benign	0.0	N;N
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-0.21	N;N
REVEL	Benign	0.10
Sift	Benign	0.46	T;T
Sift4G	Benign	0.40	T;T
Polyphen		0.18	B;B
Vest4		0.11
MutPred		0.24		Gain of loop (P = 0.1073);Gain of loop (P = 0.1073);
MVP		0.60
MPC		0.89
ClinPred		0.023	T
GERP RS		-4.5
Varity_R		0.046
gMVP		0.45

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: rs776569822; hg19: chr5-1294250; COSMIC: COSV57210617; COSMIC: COSV57210617;