rs34094720

Variant names:

• chr5-1293652-G-A
• rs34094720
• NM_198253.3:c.1234C>T

Your query was ambiguous. Multiple possible variants found:

• chr5-1293652-G-A
• chr5-1293652-G-C
• chr5-1293652-G-T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_198253.3(TERT):​c.1234C>T​(p.His412Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00451 in 1,561,382 control chromosomes in the GnomAD database, including 20 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H412R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0031 (3 hom., cov: 34)
  • Exomes 𝑓: 0.0047 (17 hom.)
• Consequence: TERT NM_198253.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:1 B:14 O:1
• Conservation: PhyloP100: 0.551
• Publications: 47 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)

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.017623723).
• BP6: Variant 5-1293652-G-A is Benign according to our data. Variant chr5-1293652-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 12730.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00308 (469/152352) while in subpopulation NFE AF = 0.00491 (334/68026). AF 95% confidence interval is 0.00448. There are 3 homozygotes in GnomAd4. There are 210 alleles in the male GnomAd4 subpopulation. Median coverage is 34. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 3 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.1234C>T	p.His412Tyr	missense	Exon 2 of 16	NP_937983.2	O14746-1
	TERT	NM_001193376.3		c.1234C>T	p.His412Tyr	missense	Exon 2 of 15	NP_001180305.1	O14746-3
	TERT	NR_149162.3		n.1313C>T		non_coding_transcript_exon	Exon 2 of 13

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TERT	ENST00000310581.10	TSL:1 MANE Select	c.1234C>T	p.His412Tyr	missense	Exon 2 of 16	ENSP00000309572.5	O14746-1
	TERT	ENST00000334602.10	TSL:1	c.1234C>T	p.His412Tyr	missense	Exon 2 of 15	ENSP00000334346.6	O14746-3
	TERT	ENST00000460137.6	TSL:1	n.1234C>T		non_coding_transcript_exon	Exon 2 of 13	ENSP00000425003.1	O14746-4

Frequencies

GnomAD3 genomes AF: 0.00308 AC: 469 AN: 152234 Hom.: 3 Cov.: 34

Gnomad AFR AF: 0.000940

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00105

Gnomad ASJ AF: 0.0170

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00122

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00491

Gnomad OTH AF: 0.00287

GnomAD2 exomes AF: 0.00327 AC: 547 AN: 167512 AF XY: 0.00301

Gnomad AFR exome AF: 0.000641

Gnomad AMR exome AF: 0.00126

Gnomad ASJ exome AF: 0.0188

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000950

Gnomad NFE exome AF: 0.00459

Gnomad OTH exome AF: 0.00310

GnomAD4 exome AF: 0.00467 AC: 6574 AN: 1409030 Hom.: 17 Cov.: 32 AF XY: 0.00448 AC XY: 3116 AN XY: 695788

African (AFR) AF: 0.000646 AC: 21 AN: 32488

American (AMR) AF: 0.000990 AC: 36 AN: 36370

Ashkenazi Jewish (ASJ) AF: 0.0187 AC: 472 AN: 25242

East Asian (EAS) AF: 0.00 AC: 0 AN: 37122

South Asian (SAS) AF: 0.000575 AC: 46 AN: 80016

European-Finnish (FIN) AF: 0.00109 AC: 53 AN: 48436

Middle Eastern (MID) AF: 0.00158 AC: 9 AN: 5704

European-Non Finnish (NFE) AF: 0.00517 AC: 5613 AN: 1085180

Other (OTH) AF: 0.00554 AC: 324 AN: 58472

GnomAD4 genome AF: 0.00308 AC: 469 AN: 152352 Hom.: 3 Cov.: 34 AF XY: 0.00282 AC XY: 210 AN XY: 74492

African (AFR) AF: 0.000938 AC: 39 AN: 41594

American (AMR) AF: 0.00104 AC: 16 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.0170 AC: 59 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4826

European-Finnish (FIN) AF: 0.00122 AC: 13 AN: 10624

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

European-Non Finnish (NFE) AF: 0.00491 AC: 334 AN: 68026

Other (OTH) AF: 0.00284 AC: 6 AN: 2116

Alfa AF: 0.00480 Hom.: 7

Bravo AF: 0.00323

TwinsUK AF: 0.00485 AC: 18

ALSPAC AF: 0.00441 AC: 17

ESP6500AA AF: 0.000936 AC: 4

ESP6500EA AF: 0.00426 AC: 36

ExAC AF: 0.00224 AC: 258

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	3	not provided (4)
-	-	4	not specified (4)
-	-	2	Dyskeratosis congenita (2)
1	-	1	Pulmonary fibrosis and/or bone marrow failure, Telomere-related, 1 (2)
-	-	1	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 (1)
-	-	1	Aplastic anemia (2)
1	-	-	Autosomal recessive dyskeratosis congenita 4 (1)
-	-	1	Dyskeratosis congenita, autosomal dominant 2 (1)
-	-	1	Idiopathic Pulmonary Fibrosis;C3151443:Dyskeratosis congenita, autosomal dominant 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.080
BayesDel_addAF	Benign	-0.062	T
BayesDel_noAF	Pathogenic	0.14
CADD	Benign	19
DANN	Uncertain	1.0
DEOGEN2	Benign	0.40	T
Eigen	Benign	-0.28
Eigen_PC	Benign	-0.33
FATHMM_MKL	Benign	0.51	D
LIST_S2	Benign	0.85	T
MetaRNN	Benign	0.018	T
MetaSVM	Uncertain	0.56	D
MutationAssessor	Uncertain	2.7	M
PhyloP100		0.55
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-2.1	N
REVEL	Pathogenic	0.67
Sift	Benign	0.65	T
Sift4G	Benign	0.063	T
Polyphen		1.0	D
Vest4		0.43
MVP		0.95
MPC		1.3
ClinPred		0.022	T
GERP RS		2.3
Varity_R		0.060
gMVP		0.64
Mutation Taster		=79/21	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: rs34094720; hg19: chr5-1293767; COSMIC: COSV57234896; COSMIC: COSV57234896;