5-1290204-T-G

Variant names:

• chr5-1290204-T-G
• rs62332591
• NM_198253.3:c.1573+3109A>C

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_198253.3(TERT):​c.1573+3109A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.44 (1036 hom., cov: 0)
• Consequence: TERT NM_198253.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.64
• Publications: 4 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: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.07).
• BS2: High Homozygotes in GnomAd4 at 1036 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TERT	NM_198253.3	MANE Select	c.1573+3109A>C		intron	N/A	NP_937983.2
	TERT	NM_001193376.3		c.1573+3109A>C		intron	N/A	NP_001180305.1
	TERT	NR_149162.3		n.1652+3109A>C		intron	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TERT	ENST00000310581.10	TSL:1 MANE Select	c.1573+3109A>C		intron	N/A	ENSP00000309572.5
	TERT	ENST00000334602.10	TSL:1	c.1573+3109A>C		intron	N/A	ENSP00000334346.6
	TERT	ENST00000460137.6	TSL:1	n.1573+3109A>C		intron	N/A	ENSP00000425003.1

Frequencies

GnomAD3 genomes AF: 0.438 AC: 8734 AN: 19920 Hom.: 1035 Cov.: 0

Gnomad AFR AF: 0.402

Gnomad AMI AF: 0.333

Gnomad AMR AF: 0.510

Gnomad ASJ AF: 0.383

Gnomad EAS AF: 0.424

Gnomad SAS AF: 0.323

Gnomad FIN AF: 0.441

Gnomad MID AF: 0.0714

Gnomad NFE AF: 0.445

Gnomad OTH AF: 0.392

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.439 AC: 8737 AN: 19922 Hom.: 1036 Cov.: 0 AF XY: 0.446 AC XY: 4357 AN XY: 9770

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

African (AFR) AF: 0.401 AC: 906 AN: 2258

American (AMR) AF: 0.511 AC: 1086 AN: 2124

Ashkenazi Jewish (ASJ) AF: 0.383 AC: 260 AN: 678

East Asian (EAS) AF: 0.424 AC: 291 AN: 686

South Asian (SAS) AF: 0.324 AC: 189 AN: 584

European-Finnish (FIN) AF: 0.441 AC: 456 AN: 1034

Middle Eastern (MID) AF: 0.0714 AC: 1 AN: 14

European-Non Finnish (NFE) AF: 0.445 AC: 5393 AN: 12132

Other (OTH) AF: 0.393 AC: 117 AN: 298

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.1
CADD	Benign	3.4
DANN	Benign	0.48
PhyloP100		-1.6
Mutation Taster		=100/0	polymorphism (auto)

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: rs62332591; hg19: chr5-1290319;