rs114012142

Variant names:

• chr5-1253575-G-A
• rs114012142
• NM_198253.3:c.*153C>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_198253.3(TERT):​c.*153C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00165 in 679,646 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0052 (5 hom., cov: 33)
  • Exomes 𝑓: 0.00063 (0 hom.)
• Consequence: TERT NM_198253.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:3
• Conservation: PhyloP100: 0.0820
• 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: 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

ENSG00000287486 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 5-1253575-G-A is Benign according to our data. Variant chr5-1253575-G-A is described in ClinVar as [Benign]. Clinvar id is 350513.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00519 (790/152348) while in subpopulation AFR AF = 0.018 (747/41588). AF 95% confidence interval is 0.0169. There are 5 homozygotes in GnomAd4. There are 380 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 5 AR,AD,SD,Unknown gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TERT	NM_198253.3	c.*153C>T		3_prime_UTR_variant	Exon 16 of 16	ENST00000310581.10	NP_937983.2
TERT	NR_149162.3	n.3260C>T		non_coding_transcript_exon_variant	Exon 13 of 13
TERT	NR_149163.3	n.3224C>T		non_coding_transcript_exon_variant	Exon 13 of 13
TERT	NM_001193376.3	c.*153C>T		3_prime_UTR_variant	Exon 15 of 15		NP_001180305.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TERT	ENST00000310581.10	c.*153C>T		3_prime_UTR_variant	Exon 16 of 16	1	NM_198253.3	ENSP00000309572.5

Frequencies

GnomAD3 genomes AF: 0.00513 AC: 781 AN: 152230 Hom.: 4 Cov.: 33

Gnomad AFR AF: 0.0178

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00164

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.00430

GnomAD4 exome AF: 0.000632 AC: 333 AN: 527298 Hom.: 0 Cov.: 6 AF XY: 0.000489 AC XY: 136 AN XY: 278044

African (AFR) AF: 0.0174 AC: 266 AN: 15270

American (AMR) AF: 0.000397 AC: 12 AN: 30254

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 16422

East Asian (EAS) AF: 0.00 AC: 0 AN: 31648

South Asian (SAS) AF: 0.0000189 AC: 1 AN: 52992

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 31550

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2254

European-Non Finnish (NFE) AF: 0.0000629 AC: 20 AN: 317840

Other (OTH) AF: 0.00117 AC: 34 AN: 29068

GnomAD4 genome AF: 0.00519 AC: 790 AN: 152348 Hom.: 5 Cov.: 33 AF XY: 0.00510 AC XY: 380 AN XY: 74492

African (AFR) AF: 0.0180 AC: 747 AN: 41588

American (AMR) AF: 0.00163 AC: 25 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3464

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000118 AC: 8 AN: 68028

Other (OTH) AF: 0.00426 AC: 9 AN: 2114

Alfa AF: 0.00317 Hom.: 0

Bravo AF: 0.00606

Asia WGS AF: 0.00289 AC: 10 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, single submitter

Submissions by phenotype

Aplastic anemia Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Dyskeratosis congenita, autosomal dominant 2 Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

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

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	3.6
DANN	Benign	0.92
PhyloP100		0.082
Mutation Taster		=100/0	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: rs114012142; hg19: chr5-1253690;