rs544215765

Variant names:

• chr5-1294797-G-A
• NM_198253.3:c.193C>T

Your query was ambiguous. Multiple possible variants found:

• chr5-1294797-G-A
• chr5-1294797-G-C
• chr5-1294797-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 6P and 1B. PM1 PM2 PM5 BP4

The NM_198253.3(TERT):​c.193C>T​(p.Pro65Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000219 in 1,372,134 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P65A) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000022 (0 hom.)
• Consequence: TERT NM_198253.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.882

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 5 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
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr5-1294797-G-C is described in Lovd as [Pathogenic].
• BP4: Computational evidence support a benign effect (MetaRNN=0.35174435).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TERT	NM_198253.3	c.193C>T	p.Pro65Ser	missense_variant	Exon 1 of 16	ENST00000310581.10	NP_937983.2
TERT	NM_001193376.3	c.193C>T	p.Pro65Ser	missense_variant	Exon 1 of 15		NP_001180305.1
TERT	NR_149162.3	n.272C>T		non_coding_transcript_exon_variant	Exon 1 of 13
TERT	NR_149163.3	n.272C>T		non_coding_transcript_exon_variant	Exon 1 of 13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TERT	ENST00000310581.10	c.193C>T	p.Pro65Ser	missense_variant	Exon 1 of 16	1	NM_198253.3	ENSP00000309572.5
TERT	ENST00000334602.10	c.193C>T	p.Pro65Ser	missense_variant	Exon 1 of 15	1		ENSP00000334346.6
TERT	ENST00000460137.6	n.193C>T		non_coding_transcript_exon_variant	Exon 1 of 13	1		ENSP00000425003.1
TERT	ENST00000656021.1	n.193C>T		non_coding_transcript_exon_variant	Exon 1 of 17			ENSP00000499759.1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 0.00000219 AC: 3 AN: 1372134 Hom.: 0 Cov.: 35 AF XY: 0.00000148 AC XY: 1 AN XY: 677132

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: 0.00000186

Gnomad4 OTH exome AF: 0.0000175

GnomAD4 genome Cov.: 34

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Uncertain	0.028	T
BayesDel_noAF	Benign	-0.20
CADD	Benign	16
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.46	T;.
Eigen	Benign	-0.14
Eigen_PC	Benign	-0.20
FATHMM_MKL	Benign	0.021	N
LIST_S2	Benign	0.81	T;T
M_CAP	Pathogenic	0.98	D
MetaRNN	Benign	0.35	T;T
MetaSVM	Uncertain	0.070	D
MutationAssessor	Uncertain	2.4	M;M
PrimateAI	Pathogenic	0.85	D
PROVEAN	Benign	-2.0	N;N
REVEL	Uncertain	0.29
Sift	Benign	0.061	T;T
Sift4G	Uncertain	0.023	D;D
Polyphen		0.69	P;P
Vest4		0.17
MVP		0.78
MPC		1.2
ClinPred		0.30	T
GERP RS		3.1
Varity_R		0.080
gMVP		0.58

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr5-1294912;