chr5-1260600-G-T

Position:

• chr5-1260600-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM1 PM2 BP4

The NM_198253.3(TERT):​c.2844C>A​(p.Ser948Arg) variant causes a missense, splice region 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. 13/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 33)
• Consequence: TERT NM_198253.3 missense, splice_region
• Scores: Splicing: ADA: 0.00004077
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.301

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 3 ACMG points.

• PM1: In a region_of_interest CTE (size 196) in uniprot entity TERT_HUMAN there are 17 pathogenic changes around while only 4 benign (81%) in NM_198253.3
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.42230558).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TERT	NM_198253.3	c.2844C>A	p.Ser948Arg	missense_variant, splice_region_variant	12/16	ENST00000310581.10	NP_937983.2
TERT	NM_001193376.3	c.2655C>A	p.Ser885Arg	missense_variant, splice_region_variant	11/15		NP_001180305.1
TERT	NR_149162.3	n.2552C>A		splice_region_variant, non_coding_transcript_exon_variant	9/13
TERT	NR_149163.3	n.2516C>A		splice_region_variant, non_coding_transcript_exon_variant	9/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TERT	ENST00000310581.10	c.2844C>A	p.Ser948Arg	missense_variant, splice_region_variant	12/16	1	NM_198253.3	ENSP00000309572	P2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.52
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Benign	-0.090
CADD	Benign	3.2
DANN	Benign	0.95
DEOGEN2	Benign	0.33	T;.
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.3
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Benign	0.73	T;T
M_CAP	Uncertain	0.25	D
MetaRNN	Benign	0.42	T;T
MetaSVM	Uncertain	-0.081	T
MutationAssessor	Benign	1.1	L;.
MutationTaster	Benign	1.0	D;D;N
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-0.97	N;N
REVEL	Uncertain	0.37
Sift	Benign	0.11	T;T
Sift4G	Benign	0.24	T;T
Polyphen		0.49	P;B
Vest4		0.43
MutPred		0.19		Gain of MoRF binding (P = 0.012);Gain of MoRF binding (P = 0.0124);
MVP		0.72
MPC		1.2
ClinPred		0.48	T
GERP RS		-6.3
RBP_binding_hub_radar		0.67
RBP_regulation_power_radar		2.4
Varity_R		0.10
gMVP		0.65

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000041
dbscSNV1_RF	Benign	0.024
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: rs34062885; hg19: chr5-1260715;