5-1279431-C-G

Position:

• chr5-1279431-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP5 BP4

The NM_198253.3(TERT):​c.1990G>C​(p.Val664Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: TERT NM_198253.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:3
• Conservation: PhyloP100: 1.73

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 5-1279431-C-G is Pathogenic according to our data. Variant chr5-1279431-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 212400.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=3, Likely_pathogenic=2}.
• BP4: Computational evidence support a benign effect (MetaRNN=0.42041147). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TERT	NM_198253.3	c.1990G>C	p.Val664Leu	missense_variant	5/16	ENST00000310581.10	NP_937983.2
TERT	NM_001193376.3	c.1990G>C	p.Val664Leu	missense_variant	5/15		NP_001180305.1
TERT	NR_149162.3	n.2069G>C		non_coding_transcript_exon_variant	5/13
TERT	NR_149163.3	n.2069G>C		non_coding_transcript_exon_variant	5/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TERT	ENST00000310581.10	c.1990G>C	p.Val664Leu	missense_variant	5/16	1	NM_198253.3	ENSP00000309572.5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000651 AC: 1 AN: 153646 Hom.: 0 AF XY: 0.0000121 AC XY: 1 AN XY: 82324

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

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: 0.0000171

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1398674 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 690150

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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 Cov.: 33

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2023	TERT: PM2, PM5 -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Feb 17, 2023	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 35106810, 31426295, 29463756, 33718801, 33035329) -

Myelodysplasia Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Godley laboratory, The University of Chicago

May 18, 2020

This heterozygous variant was found in a patient with MDS and complex karyotype diagnosed at age 56. The variant segregates with disease in family members (pancytopenia with macrocytosis, MDS). The following ACMG/AMP criteria were used: PS4_moderate, PM2, PM1, PP1, PP2. -

Dyskeratosis congenita, autosomal dominant 2 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Jan 15, 2016

- -

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

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 18, 2021

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. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 212400). This missense change has been observed in individual(s) with unspecified short telomere phenotype or suspected of having an inherited bone marrow failure syndrome (PMID: 29463756, 33718801). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces valine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 664 of the TERT protein (p.Val664Leu). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.50
BayesDel_addAF	Uncertain	0.087	D
BayesDel_noAF	Benign	-0.11
CADD	Benign	13
DANN	Benign	0.87
DEOGEN2	Uncertain	0.62	D;.
Eigen	Benign	-0.67
Eigen_PC	Benign	-0.72
FATHMM_MKL	Benign	0.38	N
LIST_S2	Benign	0.73	T;T
M_CAP	Pathogenic	0.66	D
MetaRNN	Benign	0.42	T;T
MetaSVM	Uncertain	0.69	D
MutationAssessor	Uncertain	2.5	M;M
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	-2.2	N;N
REVEL	Uncertain	0.42
Sift	Benign	0.099	T;D
Sift4G	Benign	0.079	T;T
Polyphen		0.37	B;B
Vest4		0.25
MutPred		0.55		Loss of methylation at K659 (P = 0.0685);Loss of methylation at K659 (P = 0.0685);
MVP		0.66
MPC		1.5
ClinPred		0.35	T
GERP RS		2.9
Varity_R		0.066
gMVP		0.94

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: rs797046042; hg19: chr5-1279546;