rs778496417

Variant names:

• chr5-1279447-C-T
• rs778496417
• NM_198253.3:c.1974G>A
• TERT p.Val658Val

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Strong BP6 BP7

The NM_198253.3(TERT):​c.1974G>A​(p.Val658Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000101 in 1,550,142 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 0.000079 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00010 (0 hom.)
• Consequence: TERT NM_198253.3 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:5
• Conservation: PhyloP100: -0.803
• Publications: 1 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):

• dyskeratosis congenita, autosomal dominant 2

  Inheritance: AD, SD, AR, Unknown Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Genomics England PanelApp, Ambry Genetics, ClinGen, G2P, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), PanelApp Australia
• pulmonary fibrosis and/or bone marrow failure, Telomere-related, 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: PanelApp Australia, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• 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)

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 5-1279447-C-T is Benign according to our data. Variant chr5-1279447-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 416276.
• BP7: Synonymous conserved (PhyloP=-0.803 with no splicing effect.

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.1974G>A	p.Val658Val	synonymous	Exon 5 of 16	NP_937983.2	O14746-1
	TERT	NM_001193376.3		c.1974G>A	p.Val658Val	synonymous	Exon 5 of 15	NP_001180305.1	O14746-3
	TERT	NR_149162.3		n.2053G>A		non_coding_transcript_exon	Exon 5 of 13

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TERT	ENST00000310581.10	TSL:1 MANE Select	c.1974G>A	p.Val658Val	synonymous	Exon 5 of 16	ENSP00000309572.5	O14746-1
	TERT	ENST00000334602.10	TSL:1	c.1974G>A	p.Val658Val	synonymous	Exon 5 of 15	ENSP00000334346.6	O14746-3
	TERT	ENST00000460137.6	TSL:1	n.1974G>A		non_coding_transcript_exon	Exon 5 of 13	ENSP00000425003.1	O14746-4

Frequencies

GnomAD3 genomes AF: 0.0000788 AC: 12 AN: 152196 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000724 AC: 11 AN: 151966 AF XY: 0.0000737

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000651

Gnomad NFE exome AF: 0.000157

Gnomad OTH exome AF: 0.000231

GnomAD4 exome AF: 0.000103 AC: 144 AN: 1397946 Hom.: 0 Cov.: 33 AF XY: 0.000100 AC XY: 69 AN XY: 689690

African (AFR) AF: 0.0000632 AC: 2 AN: 31650

American (AMR) AF: 0.00 AC: 0 AN: 35886

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25184

East Asian (EAS) AF: 0.00 AC: 0 AN: 35886

South Asian (SAS) AF: 0.00 AC: 0 AN: 79298

European-Finnish (FIN) AF: 0.0000208 AC: 1 AN: 47976

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4266

European-Non Finnish (NFE) AF: 0.000128 AC: 138 AN: 1079918

Other (OTH) AF: 0.0000518 AC: 3 AN: 57882

GnomAD4 genome AF: 0.0000788 AC: 12 AN: 152196 Hom.: 0 Cov.: 33 AF XY: 0.0000942 AC XY: 7 AN XY: 74348

African (AFR) AF: 0.0000241 AC: 1 AN: 41450

American (AMR) AF: 0.0000654 AC: 1 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000147 AC: 10 AN: 68020

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.000132 Hom.: 0

Bravo AF: 0.0000831

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	1.1
DANN	Benign	0.63
PhyloP100		-0.80
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

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.

Other links and lift over

dbSNP: rs778496417;

hg19: chr5-1279562;