rs35387865

Variant names:

• chr5-1255729-C-T
• rs35387865
• NM_198253.3:c.3033-318G>A

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.3033-318G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00884 in 152,296 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency: Genomes: 𝑓 0.0088 (7 hom., cov: 32)
• Consequence: TERT NM_198253.3 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -3.21
• Publications: 0 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=-1.04).
• BP6: Variant 5-1255729-C-T is Benign according to our data. Variant chr5-1255729-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 1218807.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00884 (1346/152296) while in subpopulation NFE AF = 0.0136 (922/67998). AF 95% confidence interval is 0.0128. There are 7 homozygotes in GnomAd4. There are 678 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 7 AR,AD,SD,Unknown gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TERT	NM_198253.3	c.3033-318G>A		intron_variant	Intron 13 of 15	ENST00000310581.10	NP_937983.2
TERT	NM_001193376.3	c.2844-318G>A		intron_variant	Intron 12 of 14		NP_001180305.1
TERT	NR_149162.3	n.2741-318G>A		intron_variant	Intron 10 of 12
TERT	NR_149163.3	n.2705-318G>A		intron_variant	Intron 10 of 12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TERT	ENST00000310581.10	c.3033-318G>A		intron_variant	Intron 13 of 15	1	NM_198253.3	ENSP00000309572.5

Frequencies

GnomAD3 genomes AF: 0.00885 AC: 1347 AN: 152178 Hom.: 7 Cov.: 32

Gnomad AFR AF: 0.00244

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.00517

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.0205

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0136

Gnomad OTH AF: 0.00908

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.00884 AC: 1346 AN: 152296 Hom.: 7 Cov.: 32 AF XY: 0.00910 AC XY: 678 AN XY: 74468

African (AFR) AF: 0.00243 AC: 101 AN: 41574

American (AMR) AF: 0.00516 AC: 79 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00104 AC: 5 AN: 4826

European-Finnish (FIN) AF: 0.0205 AC: 218 AN: 10618

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

European-Non Finnish (NFE) AF: 0.0136 AC: 922 AN: 67998

Other (OTH) AF: 0.00899 AC: 19 AN: 2114

Alfa AF: 0.0102 Hom.: 0

Bravo AF: 0.00747

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Jan 02, 2019

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.32
DANN	Benign	0.51
PhyloP100		-3.2
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: rs35387865; hg19: chr5-1255844;