5-1253629-G-A

Variant names:

• chr5-1253629-G-A
• rs2853690
• NM_198253.3:c.*99C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_198253.3(TERT):​c.*99C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.167 in 998,776 control chromosomes in the GnomAD database, including 16,193 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.19 (3360 hom., cov: 33)
  • Exomes 𝑓: 0.16 (12833 hom.)
• Consequence: TERT NM_198253.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -1.49
• Publications: 26 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

ENSG00000287486 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.98).
• BP6: Variant 5-1253629-G-A is Benign according to our data. Variant chr5-1253629-G-A is described in ClinVar as Benign. ClinVar VariationId is 350515.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.298 is higher than 0.05.

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.*99C>T		3_prime_UTR	Exon 16 of 16	NP_937983.2	O14746-1
	TERT	NM_001193376.3		c.*99C>T		3_prime_UTR	Exon 15 of 15	NP_001180305.1	O14746-3
	TERT	NR_149162.3		n.3206C>T		non_coding_transcript_exon	Exon 13 of 13

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TERT	ENST00000310581.10	TSL:1 MANE Select	c.*99C>T		3_prime_UTR	Exon 16 of 16	ENSP00000309572.5	O14746-1
	TERT	ENST00000922986.1		c.*99C>T		3_prime_UTR	Exon 17 of 17	ENSP00000593045.1
	TERT	ENST00000922985.1		c.*99C>T		3_prime_UTR	Exon 16 of 16	ENSP00000593044.1

Frequencies

GnomAD3 genomes AF: 0.193 AC: 29371 AN: 152112 Hom.: 3357 Cov.: 33

Gnomad AFR AF: 0.303

Gnomad AMI AF: 0.158

Gnomad AMR AF: 0.141

Gnomad ASJ AF: 0.127

Gnomad EAS AF: 0.00384

Gnomad SAS AF: 0.0849

Gnomad FIN AF: 0.0902

Gnomad MID AF: 0.114

Gnomad NFE AF: 0.181

Gnomad OTH AF: 0.180

GnomAD4 exome AF: 0.162 AC: 137406 AN: 846546 Hom.: 12833 Cov.: 11 AF XY: 0.158 AC XY: 69096 AN XY: 437754

African (AFR) AF: 0.314 AC: 6857 AN: 21860

American (AMR) AF: 0.0989 AC: 3459 AN: 34966

Ashkenazi Jewish (ASJ) AF: 0.128 AC: 2756 AN: 21480

East Asian (EAS) AF: 0.00160 AC: 55 AN: 34304

South Asian (SAS) AF: 0.0870 AC: 5967 AN: 68614

European-Finnish (FIN) AF: 0.0977 AC: 3782 AN: 38714

Middle Eastern (MID) AF: 0.141 AC: 436 AN: 3098

European-Non Finnish (NFE) AF: 0.184 AC: 107503 AN: 583446

Other (OTH) AF: 0.165 AC: 6591 AN: 40064

GnomAD4 genome AF: 0.193 AC: 29409 AN: 152230 Hom.: 3360 Cov.: 33 AF XY: 0.186 AC XY: 13858 AN XY: 74432

African (AFR) AF: 0.303 AC: 12571 AN: 41516

American (AMR) AF: 0.140 AC: 2145 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.127 AC: 441 AN: 3470

East Asian (EAS) AF: 0.00366 AC: 19 AN: 5192

South Asian (SAS) AF: 0.0857 AC: 414 AN: 4828

European-Finnish (FIN) AF: 0.0902 AC: 958 AN: 10620

Middle Eastern (MID) AF: 0.122 AC: 36 AN: 294

European-Non Finnish (NFE) AF: 0.181 AC: 12305 AN: 67988

Other (OTH) AF: 0.178 AC: 376 AN: 2114

Alfa AF: 0.180 Hom.: 3855

Bravo AF: 0.202

Asia WGS AF: 0.0560 AC: 197 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Aplastic anemia (1)
-	-	1	Dyskeratosis congenita, autosomal dominant 2 (1)
-	-	1	not specified (1)
-	-	1	Pulmonary fibrosis and/or bone marrow failure, Telomere-related, 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.98
CADD	Benign	0.18
DANN	Benign	0.54
PhyloP100		-1.5
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: rs2853690; hg19: chr5-1253744;