rs181612536

Variant names:

• chr5-1255339-G-A
• rs181612536
• NM_198253.3:c.3105C>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BS1 BS2

The NM_198253.3(TERT):​c.3105C>T​(p.Val1035Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00208 in 1,614,220 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0020 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0021 (8 hom.)
• Consequence: TERT NM_198253.3 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:17
• Conservation: PhyloP100: 0.600
• Publications: 2 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: PanelApp Australia, Labcorp Genetics (formerly Invitae), Ambry Genetics
• dyskeratosis congenita, autosomal dominant 2

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

ENSG00000287486 (HGNC:58990):

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.58).
• BP6: Variant 5-1255339-G-A is Benign according to our data. Variant chr5-1255339-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 165376.
• BP7: Synonymous conserved (PhyloP=0.6 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00197 (300/152362) while in subpopulation NFE AF = 0.00342 (233/68032). AF 95% confidence interval is 0.00306. There are 0 homozygotes in GnomAd4. There are 148 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 8 AD,Unknown,SD,AR gene

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TERT	NM_198253.3	MANE Select	c.3105C>T	p.Val1035Val	synonymous	Exon 14 of 16	NP_937983.2	O14746-1
	TERT	NM_001193376.3		c.2916C>T	p.Val972Val	synonymous	Exon 13 of 15	NP_001180305.1	O14746-3
	TERT	NR_149162.3		n.2813C>T		non_coding_transcript_exon	Exon 11 of 13

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TERT	ENST00000310581.10	TSL:1 MANE Select	c.3105C>T	p.Val1035Val	synonymous	Exon 14 of 16	ENSP00000309572.5	O14746-1
	TERT	ENST00000334602.10	TSL:1	c.2916C>T	p.Val972Val	synonymous	Exon 13 of 15	ENSP00000334346.6	O14746-3
	TERT	ENST00000460137.6	TSL:1	n.*310C>T		non_coding_transcript_exon	Exon 11 of 13	ENSP00000425003.1	O14746-4

Frequencies

GnomAD3 genomes AF: 0.00197 AC: 300 AN: 152244 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00547

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00357

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00342

Gnomad OTH AF: 0.000479

GnomAD2 exomes AF: 0.00209 AC: 521 AN: 249192 AF XY: 0.00201

Gnomad AFR exome AF: 0.000129

Gnomad AMR exome AF: 0.000348

Gnomad ASJ exome AF: 0.00616

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00561

Gnomad NFE exome AF: 0.00273

Gnomad OTH exome AF: 0.00248

GnomAD4 exome AF: 0.00209 AC: 3051 AN: 1461858 Hom.: 8 Cov.: 32 AF XY: 0.00212 AC XY: 1543 AN XY: 727232

African (AFR) AF: 0.000209 AC: 7 AN: 33480

American (AMR) AF: 0.000291 AC: 13 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.00543 AC: 142 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86254

European-Finnish (FIN) AF: 0.00521 AC: 278 AN: 53410

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00224 AC: 2489 AN: 1112006

Other (OTH) AF: 0.00200 AC: 121 AN: 60396

GnomAD4 genome AF: 0.00197 AC: 300 AN: 152362 Hom.: 0 Cov.: 33 AF XY: 0.00199 AC XY: 148 AN XY: 74496

African (AFR) AF: 0.000120 AC: 5 AN: 41582

American (AMR) AF: 0.000261 AC: 4 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00547 AC: 19 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00357 AC: 38 AN: 10632

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00342 AC: 233 AN: 68032

Other (OTH) AF: 0.000474 AC: 1 AN: 2110

Alfa AF: 0.00251 Hom.: 0

Bravo AF: 0.00135

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00284

EpiControl AF: 0.00172

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	6	not provided (7)
-	-	4	not specified (4)
-	-	2	Dyskeratosis congenita (2)
-	-	1	Aplastic anemia (1)
-	-	1	DiGeorge syndrome (1)
-	-	1	Dyskeratosis congenita, autosomal dominant 2 (1)
-	-	1	Idiopathic Pulmonary Fibrosis;C3151443:Dyskeratosis congenita, autosomal dominant 2 (1)
-	-	1	Pulmonary fibrosis and/or bone marrow failure, Telomere-related, 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.58
CADD	Benign	6.8
DANN	Benign	0.52
PhyloP100		0.60
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs181612536; hg19: chr5-1255454; COSMIC: COSV57215043;