5-1271546-T-C

Variant names:

• chr5-1271546-T-C
• rs13172201
• NM_198253.3:c.2383-342A>G

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.2383-342A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.347 in 149,926 control chromosomes in the GnomAD database, including 10,530 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.35 (10530 hom., cov: 31)
• Consequence: TERT NM_198253.3 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.634
• Publications: 14 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=-0.93).
• BP6: Variant 5-1271546-T-C is Benign according to our data. Variant chr5-1271546-T-C is described in ClinVar as Benign. ClinVar VariationId is 1181061.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.847 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.2383-342A>G		intron	N/A	NP_937983.2
	TERT	NM_001193376.3		c.2383-342A>G		intron	N/A	NP_001180305.1
	TERT	NR_149162.3		n.2366-2913A>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.2383-342A>G		intron	N/A	ENSP00000309572.5
	TERT	ENST00000334602.10	TSL:1	c.2383-342A>G		intron	N/A	ENSP00000334346.6
	TERT	ENST00000460137.6	TSL:1	n.2251-2913A>G		intron	N/A	ENSP00000425003.1

Frequencies

GnomAD3 genomes AF: 0.347 AC: 51928 AN: 149808 Hom.: 10495 Cov.: 31

Gnomad AFR AF: 0.408

Gnomad AMI AF: 0.204

Gnomad AMR AF: 0.444

Gnomad ASJ AF: 0.250

Gnomad EAS AF: 0.868

Gnomad SAS AF: 0.391

Gnomad FIN AF: 0.403

Gnomad MID AF: 0.201

Gnomad NFE AF: 0.248

Gnomad OTH AF: 0.303

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

GnomAD4 genome AF: 0.347 AC: 52029 AN: 149926 Hom.: 10530 Cov.: 31 AF XY: 0.358 AC XY: 26146 AN XY: 73054

African (AFR) AF: 0.408 AC: 16595 AN: 40676

American (AMR) AF: 0.445 AC: 6696 AN: 15046

Ashkenazi Jewish (ASJ) AF: 0.250 AC: 866 AN: 3462

East Asian (EAS) AF: 0.869 AC: 4236 AN: 4876

South Asian (SAS) AF: 0.390 AC: 1849 AN: 4740

European-Finnish (FIN) AF: 0.403 AC: 4141 AN: 10282

Middle Eastern (MID) AF: 0.207 AC: 61 AN: 294

European-Non Finnish (NFE) AF: 0.248 AC: 16748 AN: 67554

Other (OTH) AF: 0.312 AC: 652 AN: 2090

Alfa AF: 0.313 Hom.: 925

Bravo AF: 0.359

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Oct 24, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	2.4
DANN	Benign	0.28
PhyloP100		-0.63
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: rs13172201; hg19: chr5-1271661;