rs774381540

Variant names:

• chr5-1279409-C-G
• rs774381540
• NM_198253.3:c.2012G>C

Your query was ambiguous. Multiple possible variants found:

• chr5-1279409-C-G
• chr5-1279409-C-T

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM1 PM2 PM5 PP3

The NM_198253.3(TERT):​c.2012G>C​(p.Arg671Pro) 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 pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R671G) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: TERT NM_198253.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.216
• 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

ACMG classification

Our verdict: Likely_pathogenic. The variant received 7 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, 15 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 chr5-1279410-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 410693.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.751

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TERT	NM_198253.3	c.2012G>C	p.Arg671Pro	missense_variant	Exon 5 of 16	ENST00000310581.10	NP_937983.2
TERT	NM_001193376.3	c.2012G>C	p.Arg671Pro	missense_variant	Exon 5 of 15		NP_001180305.1
TERT	NR_149162.3	n.2091G>C		non_coding_transcript_exon_variant	Exon 5 of 13
TERT	NR_149163.3	n.2091G>C		non_coding_transcript_exon_variant	Exon 5 of 13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TERT	ENST00000310581.10	c.2012G>C	p.Arg671Pro	missense_variant	Exon 5 of 16	1	NM_198253.3	ENSP00000309572.5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Mar 18, 2020

Genetic Services Laboratory, University of Chicago

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

DNA sequence analysis of the TERT gene demonstrated a sequence change, c.2012G>C, in exon 5 that results in an amino acid change, p.Arg671Pro. The p.Arg671Pro change affects a poorly conserved amino acid residue located in a domain of the TERT protein that is known to be functional. This sequence change is absent from the large population databases (ExAC and gnomAD). In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Arg671Pro substitution. This particular amino acid change does not appear to have been described in the literature in other patients with TERT related disorders, however, a different sequence change affecting the same amino acid residue (p.Arg671Trp) has been described in a patient with personal and family history of pulmonary fibrosis (PMID: 20502709). They also demonstrated reduction in in vitro telomerase activity for this variant measured by the telomere repeat amplification protocol (TRAP) assay. The p.Arg671Pro amino acid change also occurs in a region of the TERT gene where other missense sequence changes have been described in patients with TERT-related disorders. Due to these contrasting evidences and the lack of functional studies, the clinical significance of the p.Arg671Pro change remains unknown at this time. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.50
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Uncertain	-0.010
CADD	Benign	13
DANN	Benign	0.95
DEOGEN2	Pathogenic	0.88	D;.
Eigen	Benign	-0.45
Eigen_PC	Benign	-0.68
FATHMM_MKL	Benign	0.011	N
LIST_S2	Benign	0.54	T;T
M_CAP	Pathogenic	0.60	D
MetaRNN	Pathogenic	0.75	D;D
MetaSVM	Uncertain	0.29	D
MutationAssessor	Uncertain	2.5	M;M
PhyloP100		-0.22
PrimateAI	Benign	0.39	T
PROVEAN	Uncertain	-2.9	D;D
REVEL	Uncertain	0.51
Sift	Benign	0.21	T;T
Sift4G	Benign	0.14	T;T
Polyphen		0.96	D;P
Vest4		0.52
MutPred		0.54		Loss of MoRF binding (P = 0.0188);Loss of MoRF binding (P = 0.0188);
MVP		0.91
MPC		2.2
ClinPred		0.75	D
GERP RS		0.081
Varity_R		0.32
gMVP		0.94
Mutation Taster		=55/45	polymorphism

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: rs774381540; hg19: chr5-1279524;