rs573817924

Variant names:

• chr5-1294764-G-A
• rs573817924
• NM_198253.3:c.219+7C>T

Your query was ambiguous. Multiple possible variants found:

• chr5-1294764-G-A
• chr5-1294764-G-T

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BP6

The NM_198253.3(TERT):​c.219+7C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000631 in 1,544,544 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00035 (0 hom., cov: 34)
  • Exomes 𝑓: 0.00066 (1 hom.)
• Consequence: TERT NM_198253.3 splice_region, intron
• Scores: Splicing: ADA: 0.00001177
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:10
• Conservation: PhyloP100: -1.24
• Publications: 1 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 -5 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.61).
• BP6: Variant 5-1294764-G-A is Benign according to our data. Variant chr5-1294764-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 350805.

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.219+7C>T		splice_region intron	N/A	NP_937983.2
	TERT	NM_001193376.3		c.219+7C>T		splice_region intron	N/A	NP_001180305.1
	TERT	NR_149162.3		n.298+7C>T		splice_region intron	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TERT	ENST00000310581.10	TSL:1 MANE Select	c.219+7C>T		splice_region intron	N/A	ENSP00000309572.5
	TERT	ENST00000334602.10	TSL:1	c.219+7C>T		splice_region intron	N/A	ENSP00000334346.6
	TERT	ENST00000460137.6	TSL:1	n.219+7C>T		splice_region intron	N/A	ENSP00000425003.1

Frequencies

GnomAD3 genomes AF: 0.000348 AC: 53 AN: 152188 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.0000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000691

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000325 AC: 46 AN: 141468 AF XY: 0.000318

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000156

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000710

Gnomad OTH exome AF: 0.000245

GnomAD4 exome AF: 0.000662 AC: 921 AN: 1392248 Hom.: 1 Cov.: 35 AF XY: 0.000613 AC XY: 422 AN XY: 688432

African (AFR) AF: 0.0000648 AC: 2 AN: 30868

American (AMR) AF: 0.000214 AC: 8 AN: 37310

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25002

East Asian (EAS) AF: 0.00 AC: 0 AN: 36348

South Asian (SAS) AF: 0.00 AC: 0 AN: 79690

European-Finnish (FIN) AF: 0.0000586 AC: 2 AN: 34144

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4488

European-Non Finnish (NFE) AF: 0.000823 AC: 894 AN: 1086272

Other (OTH) AF: 0.000258 AC: 15 AN: 58126

GnomAD4 genome AF: 0.000348 AC: 53 AN: 152296 Hom.: 0 Cov.: 34 AF XY: 0.000295 AC XY: 22 AN XY: 74464

African (AFR) AF: 0.0000481 AC: 2 AN: 41580

American (AMR) AF: 0.000131 AC: 2 AN: 15298

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.0000942 AC: 1 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.000691 AC: 47 AN: 68002

Other (OTH) AF: 0.000473 AC: 1 AN: 2116

Alfa AF: 0.000323 Hom.: 0

Bravo AF: 0.000431

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	2	not specified (2)
-	-	1	Aplastic anemia (1)
-	1	-	Dyskeratosis congenita (1)
-	-	1	Dyskeratosis congenita, autosomal dominant 2 (1)
-	-	1	Idiopathic Pulmonary Fibrosis;C3151443:Dyskeratosis congenita, autosomal dominant 2 (1)
-	-	1	Intellectual disability (1)
-	-	1	Pulmonary fibrosis and/or bone marrow failure, Telomere-related, 1 (1)
-	-	1	TERT-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.61
CADD	Benign	5.1
DANN	Benign	0.49
PhyloP100		-1.2
PromoterAI		-0.018	Neutral
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000012
dbscSNV1_RF	Benign	0.0040
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: rs573817924; hg19: chr5-1294879;