5-1288432-T-C

Variant names:

• chr5-1288432-T-C
• rs2853676
• NM_198253.3:c.1573+4881A>G

GermlineCancer (beta)

Variant summary

Our verdict is Benign.

<-10 Benign

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received -12 classification points (ACMG Germline Pathogenicity v2019). BA1BP4_Strong

The NM_198253.3(TERT):c.1573+4881A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a cumulative frequency of 0.745 (AC=113,244) in the gnomAD database across 152,098 control chromosomes, including 42,299 homozygotes. The grpmax filtering allele frequency (95% CI) is 0.812. In-silico predictor (BayesDel (noAF)) classifies this variant as likely benign. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.74 (42299 hom., cov: 32)
• Consequence: TERT NM_198253.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.72
• Publications: 133 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: Ambry Genetics, PanelApp Australia, Labcorp Genetics (formerly Invitae)
• dyskeratosis congenita, autosomal dominant 2

  Inheritance: AR, AD, SD, Unknown Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Genomics England PanelApp, Ambry Genetics, Laboratory for Molecular Medicine, PanelApp Australia, ClinGen, Labcorp Genetics (formerly Invitae), G2P
• acute myeloid leukemia

  Inheritance: AD Classification: STRONG, LIMITED Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• 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: Ambry Genetics, Labcorp Genetics (formerly Invitae)

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript:

Our verdict: Benign. The variant received -12 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	BP4Computational evidence suggests no impact		Computational evidence supports benign — no pathogenic computational or splicing signal (BP4); Splicing verdict: benign (Strong).; Germline computational verdict: benign (Strong).
	BA1Stand-alone benign allele frequency (>5%)		GnomAD effective popmax AF >5% — BA1 stand-alone benign; GnomAD reliable popmax AF = 0.8117 — exceeds 5%% threshold (BA1 applied)

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_198253.3. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	TERT NM_198253.3	MANE Select	c.1573+4881A>G	intron	Intron 2 of 15	Prot: NP_937983.2 UniProt:
	TERT NM_001193376.3		c.1573+4881A>G	intron	Intron 2 of 14	Prot: NP_001180305.1 UniProt:
	TERT NR_149162.3		n.1652+4881A>G	intron	Intron 2 of 12	Prot:

TERT NM_198253.3

MANE Select

HGVSc / HGVSpc.1573+4881A>G

Exon rankIntron 2 of 15

intron

Prot: NP_937983.2UniProt: O14746-1

TERT NM_001193376.3

HGVSc / HGVSpc.1573+4881A>G

Exon rankIntron 2 of 14

intron

Prot: NP_001180305.1UniProt: O14746-3

TERT NR_149162.3

HGVSc / HGVSpn.1652+4881A>G

Exon rankIntron 2 of 12

intron

Prot:

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	TERT ENST00000310581.10	TSL:1MANE Select	c.1573+4881A>G	intron	Intron 2 of 15	Prot: ENSP00000309572.5 UniProt:
	TERT ENST00000334602.10	TSL:1	c.1573+4881A>G	intron	Intron 2 of 14	Prot: ENSP00000334346.6 UniProt:
	TERT ENST00000460137.6	TSL:1	n.1573+4881A>G	intron	Intron 2 of 12	Prot: ENSP00000425003.1 UniProt:

TERT ENST00000310581.10

TSL:1MANE Select

HGVSc / HGVSpc.1573+4881A>G

Exon rankIntron 2 of 15

intron

Prot: ENSP00000309572.5UniProt: O14746-1

TERT ENST00000334602.10

TSL:1

HGVSc / HGVSpc.1573+4881A>G

Exon rankIntron 2 of 14

intron

Prot: ENSP00000334346.6UniProt: O14746-3

TERT ENST00000460137.6

TSL:1

HGVSc / HGVSpn.1573+4881A>G

Exon rankIntron 2 of 12

intron

Prot: ENSP00000425003.1UniProt: O14746-4

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 4 sources Large-scale international reference populations
GnomAD3 genomes	AF: 0.745	AC:113150	Hom:42261	AN:151980	Cov:32
GnomAD4 genome	AF: 0.745	AC:113244	Hom:42299	AN:152098	Cov:32
TOPMed (Bravo)	AF: 0.747	AC:197692	Hom:73917	AN:264690	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.736	AC:448512	Hom:165465	AN:609618	Cov:
Local & regional cohorts 10 sources Population-specific and national genomic databases
ABraOM SABE-WGS-1171	AF: 0.717	AC:1679	Hom:605	AN:2342	Cov:
ChinaMAP Phase 1	AF: 0.832	AC:	Hom:	AN:	Cov:
Denmark Genome	AF: 0.743	AC:223	Hom:	AN:300	Cov:
GenomeAsia100K	AF: 0.732	AC:2546	Hom:	AN:3478	Cov:
Korea4K (4,157 Koreans)	AF: 0.832	AC:6020	Hom:	AN:7234	Cov:
Qatari Genome	AF: 0.534	AC:94	Hom:	AN:176	Cov:
ToMMo 61KJPN (+60KJPN MNV)	AF: 0.839	AC:103016	Hom:43296	AN:122729	Cov:
Turkish Variome	AF: 0.689	AC:1065	Hom:366	AN:1546	Cov:
UK10K	AF: 0.727	AC:5494	Hom:	AN:7562	Cov:
WBBC (Westlake BioBank for Chinese) pilot	AF: 0.835	AC:7486	Hom:3139	AN:8960	Cov:

Showing 14 sources

ClinVar

Not reported in ClinVar

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Benign	0.52
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.48
DANN	Benign	0.31
GPN-Star LLR	N/A	3.0
GPN-Star score	N/A	-1.3
Mutation Taster	N/A	100/0	polymorphism (auto)
PhyloP100	Benign	-1.7

Showing 8 of 8 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.0
SpliceAI score (max)	Benign	0.0	Details are displayed if max score is > 0.2

Showing 2 of 2 scores

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

Other links and lift over

dbSNP: rs2853676;

hg19: chr5-1288547;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar