chr5-1293971-C-T

Variant names:

• chr5-1293971-C-T
• rs2736098
• NM_198253.3:c.915G>A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_198253.3(TERT):​c.915G>A​(p.Ala305Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.275 in 1,558,002 control chromosomes in the GnomAD database, including 62,465 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. A305A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.22 (4300 hom., cov: 34)
  • Exomes 𝑓: 0.28 (58165 hom.)
• Consequence: TERT NM_198253.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:19 O:3
• Conservation: PhyloP100: -1.61
• Publications: 273 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.66).
• BP6: Variant 5-1293971-C-T is Benign according to our data. Variant chr5-1293971-C-T is described in ClinVar as Benign. ClinVar VariationId is 39126.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.61 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.442 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.915G>A	p.Ala305Ala	synonymous	Exon 2 of 16	NP_937983.2
	TERT	NM_001193376.3		c.915G>A	p.Ala305Ala	synonymous	Exon 2 of 15	NP_001180305.1
	TERT	NR_149162.3		n.994G>A		non_coding_transcript_exon	Exon 2 of 13

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TERT	ENST00000310581.10	TSL:1 MANE Select	c.915G>A	p.Ala305Ala	synonymous	Exon 2 of 16	ENSP00000309572.5
	TERT	ENST00000334602.10	TSL:1	c.915G>A	p.Ala305Ala	synonymous	Exon 2 of 15	ENSP00000334346.6
	TERT	ENST00000460137.6	TSL:1	n.915G>A		non_coding_transcript_exon	Exon 2 of 13	ENSP00000425003.1

Frequencies

GnomAD3 genomes AF: 0.223 AC: 33875 AN: 152012 Hom.: 4301 Cov.: 34

Gnomad AFR AF: 0.109

Gnomad AMI AF: 0.269

Gnomad AMR AF: 0.199

Gnomad ASJ AF: 0.280

Gnomad EAS AF: 0.359

Gnomad SAS AF: 0.459

Gnomad FIN AF: 0.208

Gnomad MID AF: 0.291

Gnomad NFE AF: 0.269

Gnomad OTH AF: 0.242

GnomAD2 exomes AF: 0.287 AC: 47433 AN: 165404 AF XY: 0.301

Gnomad AFR exome AF: 0.108

Gnomad AMR exome AF: 0.205

Gnomad ASJ exome AF: 0.272

Gnomad EAS exome AF: 0.368

Gnomad FIN exome AF: 0.216

Gnomad NFE exome AF: 0.276

Gnomad OTH exome AF: 0.276

GnomAD4 exome AF: 0.281 AC: 394774 AN: 1405872 Hom.: 58165 Cov.: 63 AF XY: 0.287 AC XY: 199470 AN XY: 695238

African (AFR) AF: 0.100 AC: 3206 AN: 31918

American (AMR) AF: 0.206 AC: 7712 AN: 37376

Ashkenazi Jewish (ASJ) AF: 0.277 AC: 7012 AN: 25294

East Asian (EAS) AF: 0.301 AC: 10868 AN: 36108

South Asian (SAS) AF: 0.478 AC: 38345 AN: 80226

European-Finnish (FIN) AF: 0.211 AC: 9266 AN: 43812

Middle Eastern (MID) AF: 0.297 AC: 1699 AN: 5718

European-Non Finnish (NFE) AF: 0.276 AC: 300258 AN: 1086980

Other (OTH) AF: 0.281 AC: 16408 AN: 58440

GnomAD4 genome AF: 0.223 AC: 33879 AN: 152130 Hom.: 4300 Cov.: 34 AF XY: 0.224 AC XY: 16634 AN XY: 74360

African (AFR) AF: 0.108 AC: 4503 AN: 41536

American (AMR) AF: 0.199 AC: 3039 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.280 AC: 972 AN: 3466

East Asian (EAS) AF: 0.359 AC: 1852 AN: 5160

South Asian (SAS) AF: 0.458 AC: 2205 AN: 4818

European-Finnish (FIN) AF: 0.208 AC: 2198 AN: 10588

Middle Eastern (MID) AF: 0.272 AC: 80 AN: 294

European-Non Finnish (NFE) AF: 0.269 AC: 18255 AN: 67946

Other (OTH) AF: 0.251 AC: 530 AN: 2114

Alfa AF: 0.258 Hom.: 3590

Bravo AF: 0.214

Asia WGS AF: 0.402 AC: 1398 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	3	not provided (4)
-	-	2	Dyskeratosis congenita, autosomal dominant 2 (2)
-	-	2	Pulmonary fibrosis and/or bone marrow failure, Telomere-related, 1 (2)
-	-	1	Acute myeloid leukemia (1)
-	-	1	Aplastic anemia (2)
-	-	1	Aplastic anemia;C0023467:Acute myeloid leukemia;C3151443:Dyskeratosis congenita, autosomal dominant 2;C3553617:Pulmonary fibrosis and/or bone marrow failure, Telomere-related, 1;C3554574:Melanoma, cutaneous malignant, susceptibility to, 9;C4551974:Dyskeratosis congenita, autosomal dominant 1;C5561926:Interstitial lung disease 2 (1)
-	-	1	Dyskeratosis congenita (1)
-	-	1	Idiopathic Pulmonary Fibrosis;C3151443:Dyskeratosis congenita, autosomal dominant 2 (1)
-	-	1	Melanoma, cutaneous malignant, susceptibility to, 9 (1)
-	-	-	Dyskeratosis congenita, autosomal dominant 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.66
CADD	Benign	3.8
DANN	Benign	0.73
PhyloP100		-1.6
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: rs2736098; hg19: chr5-1294086; COSMIC: COSV57199189; COSMIC: COSV57199189;