5-1294317-G-T

Variant names:

• chr5-1294317-G-T
• rs781435225
• NM_198253.3:c.569C>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_198253.3(TERT):​c.569C>A​(p.Ala190Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000695 in 1,437,946 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. 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. A190V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: TERT NM_198253.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.70
• Publications: 0 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: Labcorp Genetics (formerly Invitae), Ambry Genetics
• dyskeratosis congenita, autosomal dominant 2

  Inheritance: AR, AD, SD, Unknown Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Ambry Genetics, G2P, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), ClinGen, Laboratory for Molecular Medicine
• 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_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.06637755).

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TERT	NM_198253.3	MANE Select	c.569C>A	p.Ala190Asp	missense	Exon 2 of 16	NP_937983.2
	TERT	NM_001193376.3		c.569C>A	p.Ala190Asp	missense	Exon 2 of 15	NP_001180305.1
	TERT	NR_149162.3		n.648C>A		non_coding_transcript_exon	Exon 2 of 13

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TERT	ENST00000310581.10	TSL:1 MANE Select	c.569C>A	p.Ala190Asp	missense	Exon 2 of 16	ENSP00000309572.5
	TERT	ENST00000334602.10	TSL:1	c.569C>A	p.Ala190Asp	missense	Exon 2 of 15	ENSP00000334346.6
	TERT	ENST00000460137.6	TSL:1	n.569C>A		non_coding_transcript_exon	Exon 2 of 13	ENSP00000425003.1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 6.95e-7 AC: 1 AN: 1437946 Hom.: 0 Cov.: 35 AF XY: 0.00000140 AC XY: 1 AN XY: 715032

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33232

American (AMR) AF: 0.00 AC: 0 AN: 43430

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25844

East Asian (EAS) AF: 0.00 AC: 0 AN: 39098

South Asian (SAS) AF: 0.00 AC: 0 AN: 84520

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39400

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5638

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1107030

Other (OTH) AF: 0.0000167 AC: 1 AN: 59754

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 34

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Dyskeratosis congenita (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.097
BayesDel_addAF	Uncertain	0.035	T
BayesDel_noAF	Benign	-0.19
CADD	Benign	1.9
DANN	Benign	0.44
DEOGEN2	Benign	0.38	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.040	N
LIST_S2	Benign	0.61	T
M_CAP	Uncertain	0.12	D
MetaRNN	Benign	0.066	T
MetaSVM	Uncertain	-0.052	T
MutationAssessor	Benign	1.3	L
PhyloP100		-1.7
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-0.89	N
REVEL	Benign	0.19
Sift	Benign	0.49	T
Sift4G	Benign	0.41	T
Polyphen		0.012	B
Vest4		0.15
MutPred		0.29		Gain of relative solvent accessibility (P = 0.005)
MVP		0.52
MPC		1.5
ClinPred		0.044	T
GERP RS		1.8
Varity_R		0.14
gMVP		0.71
Mutation Taster		=37/63	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: rs781435225; hg19: chr5-1294432;