rs368430301

Variant names:

• chr5-1279407-G-A
• rs368430301
• NM_198253.3:c.2014C>T

Your query was ambiguous. Multiple possible variants found:

• chr5-1279407-G-A
• chr5-1279407-G-C
• chr5-1279407-G-T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM1

The NM_198253.3(TERT):​c.2014C>T​(p.Arg672Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000599 in 1,552,158 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R672H) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00022 (0 hom., cov: 34)
  • Exomes 𝑓: 0.000043 (0 hom.)
• Consequence: TERT NM_198253.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: 0.462
• Publications: 3 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: Uncertain_significance. The variant received 2 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 4 benign, 25 uncertain in NM_198253.3

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.2014C>T	p.Arg672Cys	missense	Exon 5 of 16	NP_937983.2
	TERT	NM_001193376.3		c.2014C>T	p.Arg672Cys	missense	Exon 5 of 15	NP_001180305.1
	TERT	NR_149162.3		n.2093C>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.2014C>T	p.Arg672Cys	missense	Exon 5 of 16	ENSP00000309572.5
	TERT	ENST00000334602.10	TSL:1	c.2014C>T	p.Arg672Cys	missense	Exon 5 of 15	ENSP00000334346.6
	TERT	ENST00000460137.6	TSL:1	n.2014C>T		non_coding_transcript_exon	Exon 5 of 13	ENSP00000425003.1

Frequencies

GnomAD3 genomes AF: 0.000217 AC: 33 AN: 152164 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.000412

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000519 AC: 8 AN: 154134 AF XY: 0.0000603

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000898

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000676

Gnomad OTH exome AF: 0.000229

GnomAD4 exome AF: 0.0000429 AC: 60 AN: 1399994 Hom.: 0 Cov.: 33 AF XY: 0.0000434 AC XY: 30 AN XY: 691114

African (AFR) AF: 0.00 AC: 0 AN: 31736

American (AMR) AF: 0.0000554 AC: 2 AN: 36104

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25194

East Asian (EAS) AF: 0.0000277 AC: 1 AN: 36040

South Asian (SAS) AF: 0.0000629 AC: 5 AN: 79438

European-Finnish (FIN) AF: 0.0000626 AC: 3 AN: 47938

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4300

European-Non Finnish (NFE) AF: 0.0000435 AC: 47 AN: 1081298

Other (OTH) AF: 0.0000345 AC: 2 AN: 57946

GnomAD4 genome AF: 0.000217 AC: 33 AN: 152164 Hom.: 0 Cov.: 34 AF XY: 0.000269 AC XY: 20 AN XY: 74312

African (AFR) AF: 0.000121 AC: 5 AN: 41448

American (AMR) AF: 0.00 AC: 0 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5164

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

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

European-Non Finnish (NFE) AF: 0.000412 AC: 28 AN: 68022

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

Alfa AF: 0.000757 Hom.: 0

Bravo AF: 0.0000718

ESP6500AA AF: 0.000244 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000640 AC: 7

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Dyskeratosis congenita (1)
-	1	-	Idiopathic Pulmonary Fibrosis;C3151443:Dyskeratosis congenita, autosomal dominant 2 (1)
-	1	-	not provided (1)
-	1	-	TERT-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Uncertain	0.010
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.78	D
Eigen	Benign	-0.084
Eigen_PC	Benign	-0.28
FATHMM_MKL	Benign	0.031	N
LIST_S2	Benign	0.77	T
M_CAP	Pathogenic	0.71	D
MetaRNN	Uncertain	0.73	D
MetaSVM	Uncertain	0.52	D
MutationAssessor	Benign	2.0	M
PhyloP100		0.46
PrimateAI	Benign	0.40	T
PROVEAN	Uncertain	-3.3	D
REVEL	Uncertain	0.44
Sift	Benign	0.10	T
Sift4G	Uncertain	0.017	D
Polyphen		1.0	D
Vest4		0.53
MVP		0.80
MPC		1.4
ClinPred		0.36	T
GERP RS		3.8
Varity_R		0.13
gMVP		0.85
Mutation Taster		=12/88	disease causing

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: rs368430301; hg19: chr5-1279522; COSMIC: COSV109420643;