rs33956095

Variant names:

• chr5-1279390-G-A
• rs33956095
• NM_198253.3:c.2031C>T

Your query was ambiguous. Multiple possible variants found:

• chr5-1279390-G-A
• chr5-1279390-G-T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_198253.3(TERT):​c.2031C>T​(p.Gly677Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0113 in 1,557,728 control chromosomes in the GnomAD database, including 158 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. G677G) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.020 (51 hom., cov: 34)
  • Exomes 𝑓: 0.010 (107 hom.)
• Consequence: TERT NM_198253.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:16
• Conservation: PhyloP100: -2.69
• Publications: 9 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, Labcorp Genetics (formerly Invitae)
• dyskeratosis congenita, autosomal dominant 2

  Inheritance: SD, AR, AD, Unknown Classification: DEFINITIVE, STRONG, MODERATE Submitted by: ClinGen, Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine, Genomics England PanelApp
• 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=-0.78).
• BP6: Variant 5-1279390-G-A is Benign according to our data. Variant chr5-1279390-G-A is described in ClinVar as Benign. ClinVar VariationId is 227096.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.69 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0201 (3061/152282) while in subpopulation AFR AF = 0.0467 (1941/41554). AF 95% confidence interval is 0.045. There are 51 homozygotes in GnomAd4. There are 1526 alleles in the male GnomAd4 subpopulation. Median coverage is 34. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 51 AR,AD,SD,Unknown 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.2031C>T	p.Gly677Gly	synonymous	Exon 5 of 16	NP_937983.2	O14746-1
	TERT	NM_001193376.3		c.2031C>T	p.Gly677Gly	synonymous	Exon 5 of 15	NP_001180305.1	O14746-3
	TERT	NR_149162.3		n.2110C>T		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.2031C>T	p.Gly677Gly	synonymous	Exon 5 of 16	ENSP00000309572.5	O14746-1
	TERT	ENST00000334602.10	TSL:1	c.2031C>T	p.Gly677Gly	synonymous	Exon 5 of 15	ENSP00000334346.6	O14746-3
	TERT	ENST00000460137.6	TSL:1	n.2031C>T		non_coding_transcript_exon	Exon 5 of 13	ENSP00000425003.1	O14746-4

Frequencies

GnomAD3 genomes AF: 0.0200 AC: 3050 AN: 152164 Hom.: 52 Cov.: 34

Gnomad AFR AF: 0.0466

Gnomad AMI AF: 0.0789

Gnomad AMR AF: 0.0116

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00415

Gnomad FIN AF: 0.0127

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.00998

Gnomad OTH AF: 0.0129

GnomAD2 exomes AF: 0.0101 AC: 1602 AN: 158400 AF XY: 0.00941

Gnomad AFR exome AF: 0.0543

Gnomad AMR exome AF: 0.00736

Gnomad ASJ exome AF: 0.00153

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0119

Gnomad NFE exome AF: 0.0108

Gnomad OTH exome AF: 0.00851

GnomAD4 exome AF: 0.0103 AC: 14514 AN: 1405446 Hom.: 107 Cov.: 33 AF XY: 0.0100 AC XY: 6941 AN XY: 694318

African (AFR) AF: 0.0496 AC: 1583 AN: 31902

American (AMR) AF: 0.00750 AC: 275 AN: 36670

Ashkenazi Jewish (ASJ) AF: 0.00202 AC: 51 AN: 25246

East Asian (EAS) AF: 0.000220 AC: 8 AN: 36398

South Asian (SAS) AF: 0.00405 AC: 323 AN: 79718

European-Finnish (FIN) AF: 0.0123 AC: 596 AN: 48324

Middle Eastern (MID) AF: 0.0104 AC: 45 AN: 4328

European-Non Finnish (NFE) AF: 0.0102 AC: 11044 AN: 1084666

Other (OTH) AF: 0.0101 AC: 589 AN: 58194

GnomAD4 genome AF: 0.0201 AC: 3061 AN: 152282 Hom.: 51 Cov.: 34 AF XY: 0.0205 AC XY: 1526 AN XY: 74444

African (AFR) AF: 0.0467 AC: 1941 AN: 41554

American (AMR) AF: 0.0116 AC: 177 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.00144 AC: 5 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5158

South Asian (SAS) AF: 0.00394 AC: 19 AN: 4820

European-Finnish (FIN) AF: 0.0127 AC: 135 AN: 10626

Middle Eastern (MID) AF: 0.0204 AC: 6 AN: 294

European-Non Finnish (NFE) AF: 0.00998 AC: 679 AN: 68020

Other (OTH) AF: 0.0128 AC: 27 AN: 2114

Alfa AF: 0.0118 Hom.: 6

Bravo AF: 0.0210

Asia WGS AF: 0.00779 AC: 27 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	4	not provided (4)
-	-	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)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	1.7
DANN	Benign	0.65
PhyloP100		-2.7
Mutation Taster		=100/0	polymorphism

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: rs33956095; hg19: chr5-1279505; COSMIC: COSV99721410;