rs61748181

chr5-1294051-C-T

Variant summary

Our verdict is Benign. Variant got -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. 14/20 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. A279P) 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:17 O:1
• Conservation: PhyloP100: -0.632

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]

ACMG classification

Verdict is Benign. Variant got -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 id is 39125.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-1294051-C-T is described in Lovd as [Benign].
• 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 male gnomad4 subpopulation. Median coverage is 34. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 57 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TERT	NM_198253.3	c.835G>A	p.Ala279Thr	missense_variant	2/16	ENST00000310581.10
TERT	NM_001193376.3	c.835G>A	p.Ala279Thr	missense_variant	2/15
TERT	NR_149162.3	n.914G>A		non_coding_transcript_exon_variant	2/13
TERT	NR_149163.3	n.914G>A		non_coding_transcript_exon_variant	2/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TERT	ENST00000310581.10	c.835G>A	p.Ala279Thr	missense_variant	2/16	1	NM_198253.3	P2
TERT	ENST00000334602.10	c.835G>A	p.Ala279Thr	missense_variant	2/15	1		A2
TERT	ENST00000460137.6	c.835G>A	p.Ala279Thr	missense_variant, NMD_transcript_variant	2/13	1
TERT	ENST00000656021.1	c.835G>A	p.Ala279Thr	missense_variant, NMD_transcript_variant	2/17

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

GnomAD3 exomes AF: 0.0225 AC: 4706 AN: 209266 Hom.: 83 AF XY: 0.0229 AC XY: 2618 AN XY: 114518

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 SAS exome AF: 0.0125

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

Gnomad4 AFR exome AF: 0.00387

Gnomad4 AMR exome AF: 0.0110

Gnomad4 ASJ exome AF: 0.0299

Gnomad4 EAS exome AF: 0.0000526

Gnomad4 SAS exome AF: 0.0139

Gnomad4 FIN exome AF: 0.0559

Gnomad4 NFE exome AF: 0.0300

Gnomad4 OTH exome AF: 0.0244

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

Gnomad4 AFR AF: 0.00524

Gnomad4 AMR AF: 0.0101

Gnomad4 ASJ AF: 0.0280

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.0112

Gnomad4 FIN AF: 0.0605

Gnomad4 NFE AF: 0.0313

Gnomad4 OTH AF: 0.0165

Alfa AF: 0.0286 Hom.: 64

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

Significance: Benign

Submissions summary: Benign:17 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:8

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 21, 2013	Ala279Thr in exon 2 of TERT: This variant is not expected to have clinical signi ficance because it has been identified in 3.0% (255/8580) of European American c hromosomes from a broad population by the NHLBI Exome Sequencing Project (http:/ /evs.gs.washington.edu/EVS; dbSNP rs61748181). -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 05, 2016	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -

Dyskeratosis congenita, autosomal dominant 2 Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Molecular Genetics, Royal Melbourne Hospital	May 04, 2023	European Non-Finnish population allele frequency is 2.81% (rs61748181, 1118/18984 alleles, 30 homozygotes in gnomAD v2.1). Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.5.1, this variant is classified as BENIGN. Following criteria are met: BA1 -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 01, 2023	- -

Aplastic anemia Benign:1 Other:1

not provided, no classification provided	literature only	GeneReviews	-	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Idiopathic Pulmonary Fibrosis;C3151443:Dyskeratosis congenita, autosomal dominant 2 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Hereditary cancer-predisposing syndrome;C0265965:Dyskeratosis congenita Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 24, 2014

This alteration is classified as benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

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

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Malignant tumor of breast Benign:1

Benign, no assertion criteria provided

clinical testing

Center of Medical Genetics and Primary Health Care

-

- -

Computational scores

Source: dbNSFP v4.3

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;T
MetaRNN	Benign	0.030	T;T
MetaSVM	Uncertain	-0.10	T
MutationAssessor	Benign	1.3	L;L
MutationTaster	Benign	2.6e-9	A;A;A;A
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-0.91	N;N
REVEL	Benign	0.16
Sift	Benign	0.39	T;T
Sift4G	Benign	0.66	T;T
Polyphen		0.98	D;B
Vest4		0.027
MPC		1.0
ClinPred		0.0068	T
GERP RS		1.6
Varity_R		0.036
gMVP		0.34

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

Publications

LitVar

Other links and lift over

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