5-1293560-GTCC-GTCCTCC

Position:

• chr5-1293560-GTCC-GTCCTCC

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PM4_Supporting

The NM_198253.3(TERT):​c.1323_1325dupGGA​(p.Glu441dup) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000143 in 1,395,096 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: TERT NM_198253.3 disruptive_inframe_insertion
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.39

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 Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_198253.3. Strenght limited to Supporting due to length of the change: 1aa.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TERT	NM_198253.3	c.1323_1325dupGGA	p.Glu441dup	disruptive_inframe_insertion	2/16	ENST00000310581.10	NP_937983.2
TERT	NM_001193376.3	c.1323_1325dupGGA	p.Glu441dup	disruptive_inframe_insertion	2/15		NP_001180305.1
TERT	NR_149162.3	n.1402_1404dupGGA		non_coding_transcript_exon_variant	2/13
TERT	NR_149163.3	n.1402_1404dupGGA		non_coding_transcript_exon_variant	2/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TERT	ENST00000310581.10	c.1323_1325dupGGA	p.Glu441dup	disruptive_inframe_insertion	2/16	1	NM_198253.3	ENSP00000309572.5
TERT	ENST00000334602.10	c.1323_1325dupGGA	p.Glu441dup	disruptive_inframe_insertion	2/15	1		ENSP00000334346.6
TERT	ENST00000460137.6	n.1323_1325dupGGA		non_coding_transcript_exon_variant	2/13	1		ENSP00000425003.1
TERT	ENST00000656021.1	n.1323_1325dupGGA		non_coding_transcript_exon_variant	2/17			ENSP00000499759.1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD3 exomes AF: 0.00000669 AC: 1 AN: 149562 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 80200

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000143 AC: 2 AN: 1395096 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 687340

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: 9.29e-7

Gnomad4 OTH exome AF: 0.0000173

GnomAD4 genome Cov.: 34

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs377639087; hg19: chr5-1293675;