NM_198253.3:c.1990G>A

Variant names:

• chr5-1279431-C-T
• rs797046042
• NM_198253.3:c.1990G>A

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM1 PM2 PM5

The NM_198253.3(TERT):​c.1990G>A​(p.Val664Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000286 in 1,398,674 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. V664L) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000029 (0 hom.)
• Consequence: TERT NM_198253.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 1.73
• Publications: 2 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: Likely_pathogenic. The variant received 6 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 4 benign, 23 uncertain in NM_198253.3
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr5-1279431-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 212400.

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.1990G>A	p.Val664Met	missense	Exon 5 of 16	NP_937983.2
	TERT	NM_001193376.3		c.1990G>A	p.Val664Met	missense	Exon 5 of 15	NP_001180305.1
	TERT	NR_149162.3		n.2069G>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.1990G>A	p.Val664Met	missense	Exon 5 of 16	ENSP00000309572.5
	TERT	ENST00000334602.10	TSL:1	c.1990G>A	p.Val664Met	missense	Exon 5 of 15	ENSP00000334346.6
	TERT	ENST00000460137.6	TSL:1	n.1990G>A		non_coding_transcript_exon	Exon 5 of 13	ENSP00000425003.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000651 AC: 1 AN: 153646 AF XY: 0.0000121

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: 0.00

Gnomad NFE exome AF: 0.0000171

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000286 AC: 4 AN: 1398674 Hom.: 0 Cov.: 33 AF XY: 0.00000145 AC XY: 1 AN XY: 690150

African (AFR) AF: 0.00 AC: 0 AN: 31670

American (AMR) AF: 0.00 AC: 0 AN: 35942

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 35952

South Asian (SAS) AF: 0.00 AC: 0 AN: 79360

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48008

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4332

European-Non Finnish (NFE) AF: 0.00000370 AC: 4 AN: 1080314

Other (OTH) AF: 0.00 AC: 0 AN: 57902

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.38
BayesDel_addAF	Uncertain	0.060	T
BayesDel_noAF	Benign	-0.15
CADD	Benign	17
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.52	D
Eigen	Benign	-0.60
Eigen_PC	Benign	-0.67
FATHMM_MKL	Benign	0.30	N
LIST_S2	Benign	0.82	T
M_CAP	Pathogenic	0.68	D
MetaRNN	Uncertain	0.62	D
MetaSVM	Uncertain	0.44	D
MutationAssessor	Benign	1.5	L
PhyloP100		1.7
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	-2.1	N
REVEL	Uncertain	0.44
Sift	Benign	0.25	T
Sift4G	Uncertain	0.046	D
Polyphen		0.97	D
Vest4		0.53
MutPred		0.53		Gain of catalytic residue at V664 (P = 0.0335)
MVP		0.65
MPC		1.8
ClinPred		0.26	T
GERP RS		2.9
Varity_R		0.031
gMVP		0.91
Mutation Taster		=15/85	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: rs797046042; hg19: chr5-1279546;