5-1280715-G-C

Variant names:

• chr5-1280715-G-C
• rs4975538
• NM_198253.3:c.1770-377C>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_198253.3(TERT):​c.1770-377C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.313 in 152,124 control chromosomes in the GnomAD database, including 7,862 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.31 (7862 hom., cov: 34)
• Consequence: TERT NM_198253.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.105
• Publications: 12 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.377 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.1770-377C>G		intron	N/A	NP_937983.2
	TERT	NM_001193376.3		c.1770-377C>G		intron	N/A	NP_001180305.1
	TERT	NR_149162.3		n.1849-377C>G		intron	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TERT	ENST00000310581.10	TSL:1 MANE Select	c.1770-377C>G		intron	N/A	ENSP00000309572.5
	TERT	ENST00000334602.10	TSL:1	c.1770-377C>G		intron	N/A	ENSP00000334346.6
	TERT	ENST00000460137.6	TSL:1	n.1770-377C>G		intron	N/A	ENSP00000425003.1

Frequencies

GnomAD3 genomes AF: 0.313 AC: 47547 AN: 152008 Hom.: 7860 Cov.: 34

Gnomad AFR AF: 0.190

Gnomad AMI AF: 0.401

Gnomad AMR AF: 0.292

Gnomad ASJ AF: 0.382

Gnomad EAS AF: 0.392

Gnomad SAS AF: 0.358

Gnomad FIN AF: 0.399

Gnomad MID AF: 0.392

Gnomad NFE AF: 0.363

Gnomad OTH AF: 0.359

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

GnomAD4 genome AF: 0.313 AC: 47559 AN: 152124 Hom.: 7862 Cov.: 34 AF XY: 0.313 AC XY: 23246 AN XY: 74362

African (AFR) AF: 0.190 AC: 7897 AN: 41534

American (AMR) AF: 0.292 AC: 4459 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.382 AC: 1325 AN: 3470

East Asian (EAS) AF: 0.391 AC: 2015 AN: 5150

South Asian (SAS) AF: 0.356 AC: 1720 AN: 4828

European-Finnish (FIN) AF: 0.399 AC: 4228 AN: 10590

Middle Eastern (MID) AF: 0.397 AC: 116 AN: 292

European-Non Finnish (NFE) AF: 0.363 AC: 24657 AN: 67942

Other (OTH) AF: 0.368 AC: 777 AN: 2114

Alfa AF: 0.223 Hom.: 566

Bravo AF: 0.299

Asia WGS AF: 0.403 AC: 1402 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	4.9
DANN	Benign	0.67
PhyloP100		-0.10
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: rs4975538; hg19: chr5-1280830;