rs387907247

Variant names:

• chr5-1294826-A-T
• rs387907247
• NM_198253.3:c.164T>A

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3 PP5

The NM_198253.3(TERT):​c.164T>A​(p.Leu55Gln) 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 Pathogenic (no stars). Synonymous variant affecting the same amino acid position (i.e. L55L) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 34)
• Consequence: TERT NM_198253.3 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1 O:1
• Conservation: PhyloP100: 2.46
• Publications: 13 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: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 5-1294826-A-T is Pathogenic according to our data. Variant chr5-1294826-A-T is described in ClinVar as Pathogenic. ClinVar VariationId is 36945.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TERT	NM_198253.3	c.164T>A	p.Leu55Gln	missense_variant	Exon 1 of 16	ENST00000310581.10	NP_937983.2
TERT	NM_001193376.3	c.164T>A	p.Leu55Gln	missense_variant	Exon 1 of 15		NP_001180305.1
TERT	NR_149162.3	n.243T>A		non_coding_transcript_exon_variant	Exon 1 of 13
TERT	NR_149163.3	n.243T>A		non_coding_transcript_exon_variant	Exon 1 of 13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TERT	ENST00000310581.10	c.164T>A	p.Leu55Gln	missense_variant	Exon 1 of 16	1	NM_198253.3	ENSP00000309572.5
TERT	ENST00000334602.10	c.164T>A	p.Leu55Gln	missense_variant	Exon 1 of 15	1		ENSP00000334346.6
TERT	ENST00000460137.6	n.164T>A		non_coding_transcript_exon_variant	Exon 1 of 13	1		ENSP00000425003.1
TERT	ENST00000656021.1	n.164T>A		non_coding_transcript_exon_variant	Exon 1 of 17			ENSP00000499759.1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 34

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1 Other:1

Revision: no assertion criteria provided

Submissions by phenotype

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

Mar 29, 2007

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Interstitial lung disease 2 Other:1

-

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.68
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.25
CADD	Pathogenic	33
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.89	D;.
Eigen	Uncertain	0.38
Eigen_PC	Uncertain	0.29
FATHMM_MKL	Benign	0.25	N
LIST_S2	Benign	0.84	T;T
M_CAP	Pathogenic	0.98	D
MetaRNN	Pathogenic	0.98	D;D
MetaSVM	Uncertain	0.57	D
MutationAssessor	Uncertain	2.4	M;M
PhyloP100		2.5
PrimateAI	Pathogenic	0.95	D
PROVEAN	Uncertain	-3.1	D;D
REVEL	Pathogenic	0.77
Sift	Uncertain	0.0090	D;D
Sift4G	Uncertain	0.0090	D;D
Polyphen		1.0	D;D
Vest4		0.71
MutPred		0.90		Gain of disorder (P = 0.0284);Gain of disorder (P = 0.0284);
MVP		1.0
MPC		2.2
ClinPred		0.92	D
GERP RS		3.9
PromoterAI		-0.026	Neutral
Varity_R		0.45
gMVP		0.84
Mutation Taster		=3/97	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.57		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.57		Position offset: -1

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

Other links and lift over

dbSNP: rs387907247; hg19: chr5-1294941;