5-1286401-C-A

Variant names:

• chr5-1286401-C-A
• rs2736100
• NM_198253.3:c.1574-3777G>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_198253.3(TERT):​c.1574-3777G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.519 in 151,908 control chromosomes in the GnomAD database, including 20,520 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.52 (20520 hom., cov: 31)
• Consequence: TERT NM_198253.3 intron
• Clinical Significance: Benign criteria provided, single submitter P:1 U:1 B:1 O:3
• Conservation: PhyloP100: -1.13
• Publications: 602 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.01).
• BP6: Variant 5-1286401-C-A is Benign according to our data. Variant chr5-1286401-C-A is described in ClinVar as Benign. ClinVar VariationId is 375480.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.587 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.1574-3777G>T		intron	N/A	NP_937983.2
	TERT	NM_001193376.3		c.1574-3777G>T		intron	N/A	NP_001180305.1
	TERT	NR_149162.3		n.1653-3777G>T		intron	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TERT	ENST00000310581.10	TSL:1 MANE Select	c.1574-3777G>T		intron	N/A	ENSP00000309572.5
	TERT	ENST00000334602.10	TSL:1	c.1574-3777G>T		intron	N/A	ENSP00000334346.6
	TERT	ENST00000460137.6	TSL:1	n.1574-3777G>T		intron	N/A	ENSP00000425003.1

Frequencies

GnomAD3 genomes AF: 0.519 AC: 78709 AN: 151790 Hom.: 20496 Cov.: 31

Gnomad AFR AF: 0.539

Gnomad AMI AF: 0.469

Gnomad AMR AF: 0.597

Gnomad ASJ AF: 0.447

Gnomad EAS AF: 0.588

Gnomad SAS AF: 0.411

Gnomad FIN AF: 0.520

Gnomad MID AF: 0.311

Gnomad NFE AF: 0.497

Gnomad OTH AF: 0.497

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

GnomAD4 genome AF: 0.519 AC: 78771 AN: 151908 Hom.: 20520 Cov.: 31 AF XY: 0.521 AC XY: 38654 AN XY: 74238

African (AFR) AF: 0.539 AC: 22326 AN: 41432

American (AMR) AF: 0.597 AC: 9124 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.447 AC: 1552 AN: 3472

East Asian (EAS) AF: 0.588 AC: 3044 AN: 5174

South Asian (SAS) AF: 0.411 AC: 1972 AN: 4800

European-Finnish (FIN) AF: 0.520 AC: 5474 AN: 10532

Middle Eastern (MID) AF: 0.317 AC: 92 AN: 290

European-Non Finnish (NFE) AF: 0.497 AC: 33725 AN: 67922

Other (OTH) AF: 0.492 AC: 1036 AN: 2106

Alfa AF: 0.501 Hom.: 83689

Bravo AF: 0.528

Asia WGS AF: 0.469 AC: 1632 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Chronic obstructive pulmonary disease (1)
-	-	1	Idiopathic Pulmonary Fibrosis;C3151443:Dyskeratosis congenita, autosomal dominant 2 (1)
-	-	-	Chronic osteomyelitis (1)
-	-	-	Combined pulmonary fibrosis-emphysema syndrome (1)
-	-	-	Interstitial lung disease 2 (1)
-	-	-	Susceptibility to severe coronavirus disease (COVID-19) (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.050
DANN	Benign	0.33
PhyloP100		-1.1
Mutation Taster		=100/0	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: rs2736100; hg19: chr5-1286516; COSMIC: COSV57244861; COSMIC: COSV57244861;