5-1253728-T-C

Variant names:

• chr5-1253728-T-C
• rs1554038048
• NM_198253.3:c.3399A>G

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2 PM4 PP5

The NM_198253.3(TERT):​c.3399A>G​(p.Ter1133Trpext*?) variant causes a stop lost 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. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: not found (cov: 33)
• Consequence: TERT NM_198253.3 stop_lost
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1
• Conservation: PhyloP100: 2.50
• Publications: 0 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):

• pulmonary fibrosis and/or bone marrow failure, Telomere-related, 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• dyskeratosis congenita, autosomal dominant 2

  Inheritance: AR, AD, SD, Unknown Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Ambry Genetics, G2P, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), ClinGen, Laboratory for Molecular Medicine
• acute myeloid leukemia

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

ENSG00000287486 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Stoplost variant in NM_198253.3 Downstream stopcodon found after 216 codons.
• PP5: Variant 5-1253728-T-C is Pathogenic according to our data. Variant chr5-1253728-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 446375.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Likely_pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TERT	NM_198253.3	c.3399A>G	p.Ter1133Trpext*?	stop_lost	Exon 16 of 16	ENST00000310581.10	NP_937983.2
TERT	NM_001193376.3	c.3210A>G	p.Ter1070Trpext*?	stop_lost	Exon 15 of 15		NP_001180305.1
TERT	NR_149162.3	n.3107A>G		non_coding_transcript_exon_variant	Exon 13 of 13
TERT	NR_149163.3	n.3071A>G		non_coding_transcript_exon_variant	Exon 13 of 13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TERT	ENST00000310581.10	c.3399A>G	p.Ter1133Trpext*?	stop_lost	Exon 16 of 16	1	NM_198253.3	ENSP00000309572.5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Pulmonary fibrosis and/or bone marrow failure, Telomere-related, 1 Pathogenic:1

Nov 23, 2017

Degerman lab, Umeå University

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Uncertain:1

Nov 08, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: TERT c.3399A>G (p.X1133TrpextX39) changes the termination codon and is predicted to lead to an extended protein with additional amino acids added to the normal C-terminus. The variant was absent in 239294 control chromosomes (gnomAD). c.3399A>G has been reported in the literature in heterozygous state in an individual affected with aplastic anemia, who had shorter telomere length and positive family history for pulmonary fibrosis (Norberg_2018); in this family the variant was also found in a heterozygous unaffected parent, who had telomeres within the lower normal range, however, variable penetrance is known for TERT-Related Disorders. These data do not allow clear conclusions about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. However, other variants affecting the C-terminal region of the protein (e.g. c.3346_*123del177 / p.Glu1116fsX, p.Phe1127Leu, p.Thr1129Pro, p.Ile1130Val) have been reported in affected individuals (HGMD), indicating the functional importance of this protein region. ClinVar contains an entry for this variant (Variation ID: 446375). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.017	T
BayesDel_noAF	Benign	-0.26
CADD	Benign	17
DANN	Benign	0.85
Eigen	Uncertain	0.66
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Uncertain	0.83	D
PhyloP100		2.5
Vest4		0.16
GERP RS		3.3
Mutation Taster		=37/163	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs1554038048; hg19: chr5-1253843;