5-1294051-C-T

Variant names:

• chr5-1294051-C-T
• rs61748181
• NM_198253.3:c.835G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_198253.3(TERT):​c.835G>A​(p.Ala279Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0271 in 1,592,140 control chromosomes in the GnomAD database, including 703 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A279V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.022 (56 hom., cov: 34)
  • Exomes 𝑓: 0.028 (647 hom.)
• Consequence: TERT NM_198253.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:18 O:1
• Conservation: PhyloP100: -0.632
• Publications: 42 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)

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.030250609).
• BP6: Variant 5-1294051-C-T is Benign according to our data. Variant chr5-1294051-C-T is described in ClinVar as Benign. ClinVar VariationId is 39125.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0219 (3339/152292) while in subpopulation NFE AF = 0.0313 (2130/68012). AF 95% confidence interval is 0.0302. There are 56 homozygotes in GnomAd4. There are 1681 alleles in the male GnomAd4 subpopulation. Median coverage is 34. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 56 AR,AD,SD,Unknown gene

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.835G>A	p.Ala279Thr	missense	Exon 2 of 16	NP_937983.2	O14746-1
	TERT	NM_001193376.3		c.835G>A	p.Ala279Thr	missense	Exon 2 of 15	NP_001180305.1	O14746-3
	TERT	NR_149162.3		n.914G>A		non_coding_transcript_exon	Exon 2 of 13

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TERT	ENST00000310581.10	TSL:1 MANE Select	c.835G>A	p.Ala279Thr	missense	Exon 2 of 16	ENSP00000309572.5	O14746-1
	TERT	ENST00000334602.10	TSL:1	c.835G>A	p.Ala279Thr	missense	Exon 2 of 15	ENSP00000334346.6	O14746-3
	TERT	ENST00000460137.6	TSL:1	n.835G>A		non_coding_transcript_exon	Exon 2 of 13	ENSP00000425003.1	O14746-4

Frequencies

GnomAD3 genomes AF: 0.0220 AC: 3341 AN: 152174 Hom.: 57 Cov.: 34

Gnomad AFR AF: 0.00526

Gnomad AMI AF: 0.00439

Gnomad AMR AF: 0.0101

Gnomad ASJ AF: 0.0280

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0116

Gnomad FIN AF: 0.0605

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0313

Gnomad OTH AF: 0.0167

GnomAD2 exomes AF: 0.0225 AC: 4706 AN: 209266 AF XY: 0.0229

Gnomad AFR exome AF: 0.00398

Gnomad AMR exome AF: 0.0103

Gnomad ASJ exome AF: 0.0298

Gnomad EAS exome AF: 0.000192

Gnomad FIN exome AF: 0.0591

Gnomad NFE exome AF: 0.0290

Gnomad OTH exome AF: 0.0249

GnomAD4 exome AF: 0.0277 AC: 39834 AN: 1439848 Hom.: 647 Cov.: 35 AF XY: 0.0273 AC XY: 19495 AN XY: 715172

African (AFR) AF: 0.00387 AC: 127 AN: 32856

American (AMR) AF: 0.0110 AC: 469 AN: 42674

Ashkenazi Jewish (ASJ) AF: 0.0299 AC: 772 AN: 25784

East Asian (EAS) AF: 0.0000526 AC: 2 AN: 38040

South Asian (SAS) AF: 0.0139 AC: 1169 AN: 83908

European-Finnish (FIN) AF: 0.0559 AC: 2675 AN: 47836

Middle Eastern (MID) AF: 0.00940 AC: 54 AN: 5742

European-Non Finnish (NFE) AF: 0.0300 AC: 33114 AN: 1103472

Other (OTH) AF: 0.0244 AC: 1452 AN: 59536

GnomAD4 genome AF: 0.0219 AC: 3339 AN: 152292 Hom.: 56 Cov.: 34 AF XY: 0.0226 AC XY: 1681 AN XY: 74458

African (AFR) AF: 0.00524 AC: 218 AN: 41564

American (AMR) AF: 0.0101 AC: 154 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.0280 AC: 97 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5182

South Asian (SAS) AF: 0.0112 AC: 54 AN: 4822

European-Finnish (FIN) AF: 0.0605 AC: 642 AN: 10616

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.0313 AC: 2130 AN: 68012

Other (OTH) AF: 0.0165 AC: 35 AN: 2116

Alfa AF: 0.0267 Hom.: 157

Bravo AF: 0.0168

TwinsUK AF: 0.0343 AC: 127

ALSPAC AF: 0.0265 AC: 102

ESP6500AA AF: 0.00457 AC: 20

ESP6500EA AF: 0.0297 AC: 255

ExAC AF: 0.0187 AC: 2242

Asia WGS AF: 0.00693 AC: 24 AN: 3476

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	8	not specified (8)
-	-	3	not provided (3)
-	-	2	Dyskeratosis congenita, autosomal dominant 2 (2)
-	-	1	Aplastic anemia (2)
-	-	1	Dyskeratosis congenita (1)
-	-	1	Idiopathic Pulmonary Fibrosis;C3151443:Dyskeratosis congenita, autosomal dominant 2 (1)
-	-	1	Malignant tumor of breast (1)
-	-	1	Pulmonary fibrosis and/or bone marrow failure, Telomere-related, 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	0.67
DANN	Uncertain	0.99
DEOGEN2	Benign	0.38	T
Eigen	Benign	-0.82
Eigen_PC	Benign	-0.94
FATHMM_MKL	Benign	0.025	N
LIST_S2	Benign	0.56	T
MetaRNN	Benign	0.030	T
MetaSVM	Uncertain	-0.10	T
MutationAssessor	Benign	1.3	L
PhyloP100		-0.63
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-0.91	N
REVEL	Benign	0.16
Sift	Benign	0.39	T
Sift4G	Benign	0.66	T
Polyphen		0.98	D
Vest4		0.027
MPC		1.0
ClinPred		0.0068	T
GERP RS		1.6
Varity_R		0.036
gMVP		0.34
Mutation Taster		=99/1	polymorphism (auto)

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: rs61748181; hg19: chr5-1294166; COSMIC: COSV57209966; COSMIC: COSV57209966;