5-1272238-C-G

Variant names:

• chr5-1272238-C-G
• NM_198253.3:c.2329G>C
• TERT p.Val777Leu

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 6P and 2B. PM1 PM2 PM5 BP4_Moderate

The NM_198253.3(TERT):​c.2329G>C​(p.Val777Leu) 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 benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V777M) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: TERT NM_198253.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.11
• Publications: 1 publications found

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 Gene-Disease associations (from GenCC):

• dyskeratosis congenita, autosomal dominant 2

  Inheritance: AD, SD, AR, Unknown Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Genomics England PanelApp, Ambry Genetics, ClinGen, G2P, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), PanelApp Australia
• pulmonary fibrosis and/or bone marrow failure, Telomere-related, 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: PanelApp Australia, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• acute myeloid leukemia

  Inheritance: AD Classification: STRONG, LIMITED Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• dyskeratosis congenita

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Hoyeraal-Hreidarsson syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• melanoma, cutaneous malignant, susceptibility to, 9

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 benign, 17 uncertain 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 chr5-1272238-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 436985.
• BP4: Computational evidence support a benign effect (MetaRNN=0.22985488).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_198253.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TERT	NM_198253.3	MANE Select	c.2329G>C	p.Val777Leu	missense	Exon 7 of 16	NP_937983.2	O14746-1
	TERT	NM_001193376.3		c.2329G>C	p.Val777Leu	missense	Exon 7 of 15	NP_001180305.1	O14746-3
	TERT	NR_149162.3		n.2366-3605G>C		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TERT	ENST00000310581.10	TSL:1 MANE Select	c.2329G>C	p.Val777Leu	missense	Exon 7 of 16	ENSP00000309572.5	O14746-1
	TERT	ENST00000334602.10	TSL:1	c.2329G>C	p.Val777Leu	missense	Exon 7 of 15	ENSP00000334346.6	O14746-3
	TERT	ENST00000460137.6	TSL:1	n.2251-3605G>C		intron	N/A	ENSP00000425003.1	O14746-4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.36
BayesDel_addAF	Uncertain	0.030	T
BayesDel_noAF	Benign	-0.19
CADD	Benign	11
DANN	Benign	0.97
DEOGEN2	Uncertain	0.50	D
Eigen	Benign	-0.60
Eigen_PC	Benign	-0.68
FATHMM_MKL	Benign	0.27	N
LIST_S2	Benign	0.78	T
M_CAP	Pathogenic	0.43	D
MetaRNN	Benign	0.23	T
MetaSVM	Uncertain	0.26	D
MutationAssessor	Benign	1.5	L
PhyloP100		1.1
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-1.5	N
REVEL	Benign	0.28
Sift	Benign	0.26	T
Sift4G	Benign	0.27	T
Varity_R		0.10
gMVP		0.76
Mutation Taster		=43/57	disease causing

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr5-1272353;