rs387907247

Positions:

• chr5-1294826-A-T

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1 PM2 PP3_Strong PP5

The NM_198253.3(TERT):​c.164T>A​(p.Leu55Gln) 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 pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 34)
• Consequence: TERT NM_198253.3 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1 O:1
• Conservation: PhyloP100: 2.46

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 Likely_pathogenic. Variant got 9 ACMG points.

• PM1: In a region_of_interest RNA-interacting domain 1 (size 229) in uniprot entity TERT_HUMAN there are 10 pathogenic changes around while only 3 benign (77%) in NM_198253.3
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.983
• PP5: Variant 5-1294826-A-T is Pathogenic according to our data. Variant chr5-1294826-A-T is described in ClinVar as [Pathogenic]. Clinvar id is 36945.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr5-1294826-A-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TERT	NM_198253.3	c.164T>A	p.Leu55Gln	missense_variant	1/16	ENST00000310581.10	NP_937983.2
TERT	NM_001193376.3	c.164T>A	p.Leu55Gln	missense_variant	1/15		NP_001180305.1
TERT	NR_149162.3	n.243T>A		non_coding_transcript_exon_variant	1/13
TERT	NR_149163.3	n.243T>A		non_coding_transcript_exon_variant	1/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TERT	ENST00000310581.10	c.164T>A	p.Leu55Gln	missense_variant	1/16	1	NM_198253.3	ENSP00000309572.5
TERT	ENST00000334602.10	c.164T>A	p.Leu55Gln	missense_variant	1/15	1		ENSP00000334346.6
TERT	ENST00000460137.6	n.164T>A		non_coding_transcript_exon_variant	1/13	1		ENSP00000425003.1
TERT	ENST00000656021.1	n.164T>A		non_coding_transcript_exon_variant	1/17			ENSP00000499759.1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 34

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1 Other:1

Revision: no assertion criteria provided

Submissions by phenotype

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

Pathogenic, no assertion criteria provided

literature only

OMIM

Mar 29, 2007

- -

Interstitial lung disease 2 Other:1

not provided, no classification provided

literature only

GeneReviews

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.68
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.25
CADD	Pathogenic	33
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.89	D;.
Eigen	Uncertain	0.38
Eigen_PC	Uncertain	0.29
FATHMM_MKL	Benign	0.25	N
LIST_S2	Benign	0.84	T;T
M_CAP	Pathogenic	0.98	D
MetaRNN	Pathogenic	0.98	D;D
MetaSVM	Uncertain	0.57	D
MutationAssessor	Uncertain	2.4	M;M
PrimateAI	Pathogenic	0.95	D
PROVEAN	Uncertain	-3.1	D;D
REVEL	Pathogenic	0.77
Sift	Uncertain	0.0090	D;D
Sift4G	Uncertain	0.0090	D;D
Polyphen		1.0	D;D
Vest4		0.71
MutPred		0.90		Gain of disorder (P = 0.0284);Gain of disorder (P = 0.0284);
MVP		1.0
MPC		2.2
ClinPred		0.92	D
GERP RS		3.9
Varity_R		0.45
gMVP		0.84

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.57		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.57		Position offset: -1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs387907247; hg19: chr5-1294941;