chr5-1255405-G-A

Variant names:

• chr5-1255405-G-A
• rs33954691
• NM_198253.3:c.3039C>T

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.3039C>T​(p.His1013His) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.113 in 1,614,092 control chromosomes in the GnomAD database, including 12,045 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.094 (935 hom., cov: 33)
  • Exomes 𝑓: 0.11 (11110 hom.)
• Consequence: TERT NM_198253.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:14 O:1
• Conservation: PhyloP100: -0.189
• Publications: 44 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.59).
• BP6: Variant 5-1255405-G-A is Benign according to our data. Variant chr5-1255405-G-A is described in ClinVar as Benign. ClinVar VariationId is 39119.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.189 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.184 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TERT	NM_198253.3	MANE Select	c.3039C>T	p.His1013His	synonymous	Exon 14 of 16	NP_937983.2	O14746-1
	TERT	NM_001193376.3		c.2850C>T	p.His950His	synonymous	Exon 13 of 15	NP_001180305.1	O14746-3
	TERT	NR_149162.3		n.2747C>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.3039C>T	p.His1013His	synonymous	Exon 14 of 16	ENSP00000309572.5	O14746-1
	TERT	ENST00000334602.10	TSL:1	c.2850C>T	p.His950His	synonymous	Exon 13 of 15	ENSP00000334346.6	O14746-3
	TERT	ENST00000460137.6	TSL:1	n.*244C>T		non_coding_transcript_exon	Exon 11 of 13	ENSP00000425003.1	O14746-4

Frequencies

GnomAD3 genomes AF: 0.0940 AC: 14308 AN: 152206 Hom.: 935 Cov.: 33

Gnomad AFR AF: 0.0232

Gnomad AMI AF: 0.0614

Gnomad AMR AF: 0.190

Gnomad ASJ AF: 0.115

Gnomad EAS AF: 0.186

Gnomad SAS AF: 0.159

Gnomad FIN AF: 0.0967

Gnomad MID AF: 0.0759

Gnomad NFE AF: 0.103

Gnomad OTH AF: 0.104

GnomAD2 exomes AF: 0.130 AC: 32473 AN: 249236 AF XY: 0.129

Gnomad AFR exome AF: 0.0207

Gnomad AMR exome AF: 0.244

Gnomad ASJ exome AF: 0.122

Gnomad EAS exome AF: 0.178

Gnomad FIN exome AF: 0.0944

Gnomad NFE exome AF: 0.102

Gnomad OTH exome AF: 0.124

GnomAD4 exome AF: 0.115 AC: 167415 AN: 1461766 Hom.: 11110 Cov.: 33 AF XY: 0.116 AC XY: 84287 AN XY: 727178

African (AFR) AF: 0.0187 AC: 627 AN: 33478

American (AMR) AF: 0.242 AC: 10797 AN: 44704

Ashkenazi Jewish (ASJ) AF: 0.120 AC: 3140 AN: 26136

East Asian (EAS) AF: 0.253 AC: 10042 AN: 39692

South Asian (SAS) AF: 0.165 AC: 14224 AN: 86248

European-Finnish (FIN) AF: 0.0935 AC: 4993 AN: 53388

Middle Eastern (MID) AF: 0.107 AC: 617 AN: 5768

European-Non Finnish (NFE) AF: 0.105 AC: 116497 AN: 1111958

Other (OTH) AF: 0.107 AC: 6478 AN: 60394

GnomAD4 genome AF: 0.0939 AC: 14300 AN: 152326 Hom.: 935 Cov.: 33 AF XY: 0.0976 AC XY: 7270 AN XY: 74488

African (AFR) AF: 0.0231 AC: 961 AN: 41590

American (AMR) AF: 0.190 AC: 2910 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.115 AC: 400 AN: 3472

East Asian (EAS) AF: 0.186 AC: 964 AN: 5184

South Asian (SAS) AF: 0.158 AC: 763 AN: 4826

European-Finnish (FIN) AF: 0.0967 AC: 1026 AN: 10614

Middle Eastern (MID) AF: 0.0714 AC: 21 AN: 294

European-Non Finnish (NFE) AF: 0.103 AC: 6985 AN: 68018

Other (OTH) AF: 0.101 AC: 214 AN: 2114

Alfa AF: 0.0938 Hom.: 857

Bravo AF: 0.0975

Asia WGS AF: 0.160 AC: 555 AN: 3478

EpiCase AF: 0.0999

EpiControl AF: 0.104

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.59
CADD	Benign	4.2
DANN	Benign	0.48
PhyloP100		-0.19
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs33954691; hg19: chr5-1255520; COSMIC: COSV57196876;