5-1279363-G-C

Variant names:

• chr5-1279363-G-C
• rs745590324
• NM_198253.3:c.2058C>G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP5_Moderate

The NM_198253.3(TERT):​c.2058C>G​(p.Ile686Met) 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 Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: TERT NM_198253.3 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: -0.0420

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 Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 5-1279363-G-C is Pathogenic according to our data. Variant chr5-1279363-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 436992.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TERT	NM_198253.3	c.2058C>G	p.Ile686Met	missense_variant	Exon 5 of 16	ENST00000310581.10	NP_937983.2
TERT	NM_001193376.3	c.2058C>G	p.Ile686Met	missense_variant	Exon 5 of 15		NP_001180305.1
TERT	NR_149162.3	n.2137C>G		non_coding_transcript_exon_variant	Exon 5 of 13
TERT	NR_149163.3	n.2137C>G		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.2058C>G	p.Ile686Met	missense_variant	Exon 5 of 16	1	NM_198253.3	ENSP00000309572.5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Dyskeratosis congenita Pathogenic:1

May 02, 2017

Genetic Services Laboratory, University of Chicago

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.26
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.040
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.59	D;.
Eigen	Benign	-0.36
Eigen_PC	Benign	-0.56
FATHMM_MKL	Benign	0.030	N
LIST_S2	Benign	0.81	T;T
M_CAP	Pathogenic	0.68	D
MetaRNN	Uncertain	0.58	D;D
MetaSVM	Uncertain	0.45	D
MutationAssessor	Benign	1.8	L;L
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-2.0	N;N
REVEL	Uncertain	0.51
Sift	Uncertain	0.0030	D;D
Sift4G	Uncertain	0.0020	D;D
Polyphen		1.0	D;P
Vest4		0.48
MutPred		0.45		Gain of MoRF binding (P = 0.09);Gain of MoRF binding (P = 0.09);
MVP		0.83
MPC		2.1
ClinPred		0.84	D
GERP RS		1.2
Varity_R		0.28
gMVP		0.98

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: rs745590324; hg19: chr5-1279478;