NM_198253.3:c.1951-205G>A

Variant names:

• chr5-1279675-C-T
• rs10069690
• NM_198253.3:c.1951-205G>A

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_198253.3(TERT):​c.1951-205G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.349 in 152,058 control chromosomes in the GnomAD database, including 10,955 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency: Genomes: 𝑓 0.35 (10955 hom., cov: 33)
• Consequence: TERT NM_198253.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3 O:1
• Conservation: PhyloP100: -1.93
• Publications: 280 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

ACMG classification

Our verdict: Benign. The variant received -16 ACMG points.

• BP6: Variant 5-1279675-C-T is Benign according to our data. Variant chr5-1279675-C-T is described in ClinVar as Benign. ClinVar VariationId is 225783.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.584 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TERT	NM_198253.3	MANE Select	c.1951-205G>A		intron	N/A	NP_937983.2
	TERT	NM_001193376.3		c.1951-205G>A		intron	N/A	NP_001180305.1
	TERT	NR_149162.3		n.2030-205G>A		intron	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TERT	ENST00000310581.10	TSL:1 MANE Select	c.1951-205G>A		intron	N/A	ENSP00000309572.5
	TERT	ENST00000334602.10	TSL:1	c.1951-205G>A		intron	N/A	ENSP00000334346.6
	TERT	ENST00000460137.6	TSL:1	n.1951-205G>A		intron	N/A	ENSP00000425003.1

Frequencies

GnomAD3 genomes AF: 0.349 AC: 53038 AN: 151940 Hom.: 10937 Cov.: 33

Gnomad AFR AF: 0.590

Gnomad AMI AF: 0.277

Gnomad AMR AF: 0.234

Gnomad ASJ AF: 0.322

Gnomad EAS AF: 0.179

Gnomad SAS AF: 0.258

Gnomad FIN AF: 0.296

Gnomad MID AF: 0.323

Gnomad NFE AF: 0.259

Gnomad OTH AF: 0.337

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

GnomAD4 genome AF: 0.349 AC: 53094 AN: 152058 Hom.: 10955 Cov.: 33 AF XY: 0.346 AC XY: 25703 AN XY: 74334

African (AFR) AF: 0.590 AC: 24455 AN: 41448

American (AMR) AF: 0.233 AC: 3568 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.322 AC: 1119 AN: 3472

East Asian (EAS) AF: 0.178 AC: 923 AN: 5172

South Asian (SAS) AF: 0.256 AC: 1234 AN: 4820

European-Finnish (FIN) AF: 0.296 AC: 3136 AN: 10600

Middle Eastern (MID) AF: 0.330 AC: 97 AN: 294

European-Non Finnish (NFE) AF: 0.259 AC: 17603 AN: 67940

Other (OTH) AF: 0.335 AC: 706 AN: 2110

Alfa AF: 0.287 Hom.: 26410

Bravo AF: 0.353

Asia WGS AF: 0.257 AC: 899 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Idiopathic Pulmonary Fibrosis;C3151443:Dyskeratosis congenita, autosomal dominant 2 (1)
-	-	-	Chronic osteomyelitis (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	7.8
DANN	Benign	0.42
PhyloP100		-1.9
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.24		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.24		Position offset: 3

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs10069690; hg19: chr5-1279790;