rs1060503011

Variant names:

• chr5-1279410-G-A
• rs1060503011
• NM_198253.3:c.2011C>T

Your query was ambiguous. Multiple possible variants found:

• chr5-1279410-G-A
• chr5-1279410-G-C

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PM1 PM5 PP5_Very_Strong

The NM_198253.3(TERT):​c.2011C>T​(p.Arg671Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000515 in 1,552,250 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R671Q) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000050 (0 hom.)
• Consequence: TERT NM_198253.3 missense
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:8
• Conservation: PhyloP100: 0.403
• Publications: 3 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: PanelApp Australia, Labcorp Genetics (formerly Invitae), Ambry Genetics
• dyskeratosis congenita, autosomal dominant 2

  Inheritance: Unknown, SD, AD, AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Laboratory for Molecular Medicine, ClinGen, Genomics England PanelApp, G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae), PanelApp Australia
• acute myeloid leukemia

  Inheritance: AD Classification: STRONG, LIMITED Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• 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: Ambry Genetics, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 4 benign, 30 uncertain in NM_198253.3
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr5-1279410-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 436994.
• PP5: Variant 5-1279410-G-A is Pathogenic according to our data. Variant chr5-1279410-G-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 410693.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.2011C>T	p.Arg671Trp	missense	Exon 5 of 16	NP_937983.2	O14746-1
	TERT	NM_001193376.3		c.2011C>T	p.Arg671Trp	missense	Exon 5 of 15	NP_001180305.1	O14746-3
	TERT	NR_149162.3		n.2090C>T		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.2011C>T	p.Arg671Trp	missense	Exon 5 of 16	ENSP00000309572.5	O14746-1
	TERT	ENST00000334602.10	TSL:1	c.2011C>T	p.Arg671Trp	missense	Exon 5 of 15	ENSP00000334346.6	O14746-3
	TERT	ENST00000460137.6	TSL:1	n.2011C>T		non_coding_transcript_exon	Exon 5 of 13	ENSP00000425003.1	O14746-4

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152190 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00 AC: 0 AN: 154284 AF XY: 0.00

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000500 AC: 7 AN: 1400060 Hom.: 0 Cov.: 33 AF XY: 0.00000434 AC XY: 3 AN XY: 691046

African (AFR) AF: 0.0000315 AC: 1 AN: 31732

American (AMR) AF: 0.00 AC: 0 AN: 36048

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25216

East Asian (EAS) AF: 0.00 AC: 0 AN: 36030

South Asian (SAS) AF: 0.00 AC: 0 AN: 79410

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48062

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4340

European-Non Finnish (NFE) AF: 0.00000555 AC: 6 AN: 1081270

Other (OTH) AF: 0.00 AC: 0 AN: 57952

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152190 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74328

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

African (AFR) AF: 0.0000241 AC: 1 AN: 41450

American (AMR) AF: 0.00 AC: 0 AN: 15286

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10632

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68024

Other (OTH) AF: 0.00 AC: 0 AN: 2090

⚠️ 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: 0.000446 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
2	-	-	not provided (2)
1	-	-	Autosomal recessive dyskeratosis congenita 4 (1)
1	-	-	Dyskeratosis congenita (1)
1	-	-	Hoyeraal-Hreidarsson syndrome;C3151444:Autosomal recessive dyskeratosis congenita 4 (1)
1	-	-	Idiopathic Pulmonary Fibrosis;C3151443:Dyskeratosis congenita, autosomal dominant 2 (1)
1	-	-	Telomere syndrome (1)
-	-	-	Pulmonary fibrosis (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.19
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.92	D
Eigen	Benign	-0.26
Eigen_PC	Benign	-0.51
FATHMM_MKL	Benign	0.025	N
LIST_S2	Uncertain	0.90	D
M_CAP	Pathogenic	0.58	D
MetaRNN	Uncertain	0.60	D
MetaSVM	Uncertain	0.31	D
MutationAssessor	Uncertain	2.5	M
PhyloP100		0.40
PrimateAI	Benign	0.42	T
PROVEAN	Uncertain	-3.8	D
REVEL	Uncertain	0.58
Sift	Benign	0.034	D
Sift4G	Uncertain	0.032	D
Polyphen		1.0	D
Vest4		0.33
MutPred		0.53		Loss of methylation at R671 (P = 0.0327)
MVP		0.97
MPC		2.0
ClinPred		0.96	D
GERP RS		1.8
Varity_R		0.062
gMVP		0.77
Mutation Taster		=23/77	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: rs1060503011; hg19: chr5-1279525;