5-1293324-C-G

Variant names:

• chr5-1293324-C-G
• NM_198253.3:c.1562G>C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_198253.3(TERT):​c.1562G>C​(p.Arg521Pro) 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 34)
• Consequence: TERT NM_198253.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.766

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
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.864

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TERT	NM_198253.3	c.1562G>C	p.Arg521Pro	missense_variant	Exon 2 of 16	ENST00000310581.10	NP_937983.2
TERT	NM_001193376.3	c.1562G>C	p.Arg521Pro	missense_variant	Exon 2 of 15		NP_001180305.1
TERT	NR_149162.3	n.1641G>C		non_coding_transcript_exon_variant	Exon 2 of 13
TERT	NR_149163.3	n.1641G>C		non_coding_transcript_exon_variant	Exon 2 of 13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TERT	ENST00000310581.10	c.1562G>C	p.Arg521Pro	missense_variant	Exon 2 of 16	1	NM_198253.3	ENSP00000309572.5
TERT	ENST00000334602.10	c.1562G>C	p.Arg521Pro	missense_variant	Exon 2 of 15	1		ENSP00000334346.6
TERT	ENST00000460137.6	n.1562G>C		non_coding_transcript_exon_variant	Exon 2 of 13	1		ENSP00000425003.1
TERT	ENST00000656021.1	n.1562G>C		non_coding_transcript_exon_variant	Exon 2 of 17			ENSP00000499759.1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 34

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.36
BayesDel_addAF	Uncertain	0.080	D
BayesDel_noAF	Benign	-0.12
CADD	Benign	20
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.73	D;.
Eigen	Benign	-0.080
Eigen_PC	Benign	-0.31
FATHMM_MKL	Benign	0.55	D
LIST_S2	Benign	0.84	T;T
M_CAP	Pathogenic	0.88	D
MetaRNN	Pathogenic	0.86	D;D
MetaSVM	Uncertain	0.58	D
MutationAssessor	Uncertain	2.7	M;M
PrimateAI	Benign	0.31	T
PROVEAN	Uncertain	-3.5	D;D
REVEL	Uncertain	0.53
Sift	Uncertain	0.0040	D;D
Sift4G	Uncertain	0.0070	D;D
Polyphen		1.0	D;D
Vest4		0.44
MutPred		0.61		Loss of MoRF binding (P = 0.0073);Loss of MoRF binding (P = 0.0073);
MVP		0.84
MPC		2.6
ClinPred		0.95	D
GERP RS		1.8
Varity_R		0.80
gMVP		0.87

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr5-1293439;