rs763381198

Variant names:

• chr5-1255328-G-A
• rs763381198
• NM_198253.3:c.3116C>T

Your query was ambiguous. Multiple possible variants found:

• chr5-1255328-G-A
• chr5-1255328-G-C

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 0P and 3B. BP4_Moderate BP6

The NM_198253.3(TERT):​c.3116C>T​(p.Thr1039Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000198 in 1,614,074 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T1039A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000018 (0 hom.)
• Consequence: TERT NM_198253.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: 1.16
• Publications: 2 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: PanelApp Australia, Labcorp Genetics (formerly Invitae), Ambry Genetics
• dyskeratosis congenita, autosomal dominant 2

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

ENSG00000287486 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -3 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.17661768).
• BP6: Variant 5-1255328-G-A is Benign according to our data. Variant chr5-1255328-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 572727.

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.3116C>T	p.Thr1039Met	missense	Exon 14 of 16	NP_937983.2	O14746-1
	TERT	NM_001193376.3		c.2927C>T	p.Thr976Met	missense	Exon 13 of 15	NP_001180305.1	O14746-3
	TERT	NR_149162.3		n.2824C>T		non_coding_transcript_exon	Exon 11 of 13

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TERT	ENST00000310581.10	TSL:1 MANE Select	c.3116C>T	p.Thr1039Met	missense	Exon 14 of 16	ENSP00000309572.5	O14746-1
	TERT	ENST00000334602.10	TSL:1	c.2927C>T	p.Thr976Met	missense	Exon 13 of 15	ENSP00000334346.6	O14746-3
	TERT	ENST00000460137.6	TSL:1	n.*321C>T		non_coding_transcript_exon	Exon 11 of 13	ENSP00000425003.1	O14746-4

Frequencies

GnomAD3 genomes AF: 0.0000328 AC: 5 AN: 152266 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000803 AC: 2 AN: 248922 AF XY: 0.0000148

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000886

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000185 AC: 27 AN: 1461808 Hom.: 0 Cov.: 32 AF XY: 0.0000220 AC XY: 16 AN XY: 727196

African (AFR) AF: 0.0000896 AC: 3 AN: 33478

American (AMR) AF: 0.0000224 AC: 1 AN: 44704

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86234

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53414

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.0000162 AC: 18 AN: 1111982

Other (OTH) AF: 0.0000497 AC: 3 AN: 60394

GnomAD4 genome AF: 0.0000328 AC: 5 AN: 152266 Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1 AN XY: 74390

African (AFR) AF: 0.000121 AC: 5 AN: 41472

American (AMR) AF: 0.00 AC: 0 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5200

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68044

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000302

ExAC AF: 0.00000825 AC: 1

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	2	-	Dyskeratosis congenita (2)
-	-	1	Idiopathic Pulmonary Fibrosis;C3151443:Dyskeratosis congenita, autosomal dominant 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.010	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	9.8
DANN	Benign	0.11
DEOGEN2	Benign	0.35	T
Eigen	Benign	-0.93
Eigen_PC	Benign	-0.93
FATHMM_MKL	Benign	0.25	N
LIST_S2	Benign	0.76	T
M_CAP	Pathogenic	0.51	D
MetaRNN	Benign	0.18	T
MetaSVM	Uncertain	-0.10	T
MutationAssessor	Benign	1.5	L
PhyloP100		1.2
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-0.11	N
REVEL	Benign	0.18
Sift	Benign	0.54	T
Sift4G	Benign	0.43	T
Polyphen		0.59	P
Vest4		0.19
MutPred		0.46		Gain of catalytic residue at V1035 (P = 0.0137)
MVP		0.48
MPC		1.2
ClinPred		0.038	T
GERP RS		0.049
Varity_R		0.018
gMVP		0.20
Mutation Taster		=87/13	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: rs763381198; hg19: chr5-1255443; COSMIC: COSV57213617;