chr16-1500444-G-T

Variant names:

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 8P and 1B. PP5_Very_StrongBS1_Supporting

The NM_016111.4(TELO2):c.1100G>T(p.Cys367Phe) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000181 in 1,609,910 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.00017 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00018 ( 0 hom. )

Consequence

TELO2
NM_016111.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:12U:1

Conservation

PhyloP100: 7.94

Publications

5 publications found

Variant links:

Genes affected

TELO2 (HGNC:29099): (telomere maintenance 2) This gene encodes a protein that functions as an S-phase checkpoint protein in the cell cycle. The protein may also play a role in DNA repair.[provided by RefSeq, Mar 2009]

TELO2 Gene-Disease associations (from GenCC):

TELO2-related intellectual disability-neurodevelopmental disorder
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, ClinGen, G2P

TELO2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

PP5

Variant 16-1500444-G-T is Pathogenic according to our data. Variant chr16-1500444-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 236225.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000171 (26/152376) while in subpopulation AMR AF = 0.000588 (9/15308). AF 95% confidence interval is 0.000306. There are 0 homozygotes in GnomAd4. There are 16 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TELO2	NM_016111.4 link	c.1100G>T	p.Cys367Phe	missense_variant	Exon 8 of 21	ENST00000262319.11	NP_057195.2	Q9Y4R8B4DXS2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TELO2	ENST00000262319.11 link	c.1100G>T	p.Cys367Phe	missense_variant	Exon 8 of 21	1	NM_016111.4	ENSP00000262319.6		Q9Y4R8
TELO2	ENST00000497339.6 link	n.1100G>T		non_coding_transcript_exon_variant	Exon 8 of 12	5		ENSP00000456383.1		H3BRS3

Frequencies

GnomAD3 genomes

AF:

0.000171

AC:

AN:

152258

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000589

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:

0.000235

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000177

AC:

AN:

237468

AF XY:

0.000162

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000534

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000209

Gnomad OTH exome

AF:

0.000346

GnomAD4 exome

AF:

0.000182

AC:

265

AN:

1457534

Hom.:

Cov.:

AF XY:

0.000159

AC XY:

115

AN XY:

724868

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33460

American (AMR)

AF:

0.000497

AC:

AN:

44302

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25944

East Asian (EAS)

AF:

0.00

AC:

AN:

39538

South Asian (SAS)

AF:

0.00

AC:

AN:

85662

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51710

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5684

European-Non Finnish (NFE)

AF:

0.000213

AC:

237

AN:

1111072

Other (OTH)

AF:

0.0000831

AC:

AN:

60162

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000171

AC:

AN:

152376

Hom.:

Cov.:

AF XY:

0.000215

AC XY:

AN XY:

74508

show subpopulations

African (AFR)

AF:

0.0000240

AC:

AN:

41592

American (AMR)

AF:

0.000588

AC:

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10632

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000235

AC:

AN:

68040

Other (OTH)

AF:

0.00

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000156

Hom.:

Bravo

AF:

0.000162

ExAC

AF:

0.000149

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:12Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

TELO2-related intellectual disability-neurodevelopmental disorder

Pathogenic:10

Jun 03, 2025

Molecular Genetics Laboratory, BC Children's and BC Women's Hospitals

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

UNC Molecular Genetics Laboratory, University of North Carolina at Chapel Hill

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

The TELO2 c.1100G>T likely pathogenic missense variant changes a single amino acid in the protein coding region from a cysteine to a phenylalanine. This variant has been reported to segregate with You-Hoover-Fong syndrome in two families and alters an amino acid conserved in vertebrates located within the TTI1 binding domain (PMID: 27132593). -

Sep 10, 2019

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 26, 2023

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

- -

Mar 28, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: TELO2 c.1100G>T (p.Cys367Phe) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00018 in 237468 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in TELO2 causing TELO2-Related Intellectual Disability-Neurodevelopmental Disorder, allowing no conclusion about variant significance. c.1100G>T has been reported in the literature in multiple compound heterozygous individuals affected with TELO2-Related Intellectual Disability-Neurodevelopmental Disorder (e.g., You_2016, Del-Prado-Sanchez_2020, Albokhari_2023). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 36797513, 32940098, 27132593). ClinVar contains an entry for this variant (Variation ID: 236225). Based on the evidence outlined above, the variant was classified as pathogenic. -

Baylor-Hopkins Center for Mendelian Genomics, Johns Hopkins University School of Medicine

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

- -

Dec 31, 2019

Revvity Omics, Revvity

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 05, 2022

DASA

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.1100G>T;p.(Cys367Phe) missense variant has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 236225; PMID: 27132593) - PS4_moderate. Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product (PMID: 27132593) - PS3_supporting. The variant is present at low allele frequencies population databases (rs202020308 – gnomAD 0.001708%; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2_supporting. The p.(Cys367Phe) was detected in trans with a pathogenic variant (PMID: 27132593) - PM3. The variant co-segregated with disease in multiple affected family members (PMID: 27132593) - PP1. In summary, the currently available evidence indicates that the variant is likely pathogenic. -

Jul 16, 2023

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with You-Hoover-Fong syndrome (MIM#616954). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from cysteine to phenylalanine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (43 heterozygotes, 0 homozygotes). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been classified as likely pathogenic, pathogenic and as a VUS by clinical laboratories in ClinVar. This variant has also been reported as compound heterozygous with other missense variants in two unrelated families with You-Hoover-Fong syndrome and an individual with moderate global developmental delay, microcephaly and other clinical features (DECIPHER, PMID: 27132593). (SP) 0903 - This variant has limited evidence for segregation with disease. It segregated with a syndromic intellectual disability disorder in a family with three affected children who were compound heterozygotes (PMID: 27132593). (SP) 1001 - This variant has strong functional evidence supporting abnormal protein function. Functional analysis using cultured fibroblasts of two unrelated patients showed a reduced amount of TELO2 protein and its partner proteins in the TTT complex (PMID: 27132593). (SP) 1205 - This variant has been shown to be maternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

not provided

Pathogenic:1

Jan 22, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces cysteine, which is neutral and slightly polar, with phenylalanine, which is neutral and non-polar, at codon 367 of the TELO2 protein (p.Cys367Phe). This variant is present in population databases (rs202020308, gnomAD 0.06%). This missense change has been observed in individuals with You-Hoover-Fong syndrome (PMID: 27132593, 32940098). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 236225). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt TELO2 protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic. -

TELO2-related disorder

Pathogenic:1

Apr 29, 2024

PreventionGenetics, part of Exact Sciences

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

The TELO2 c.1100G>T variant is predicted to result in the amino acid substitution p.Cys367Phe. This variant was reported in an individual with You-Hoover-Fong syndrome (You et al 2016. PubMed ID: 27132593). This variant is reported in 0.052% of alleles in individuals of Latino descent in gnomAD. This variant is interpreted as likely pathogenic. -

not specified

Uncertain:1

Apr 12, 2018

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Uncertain significance

Review Status:flagged submission

Collection Method:clinical testing

Variant classified as Uncertain Significance - Favor Pathogenic. The p.Cys367Phe variant in TELO2 has been reported in the 2 individuals with intellectual disab ility and segregated in 2 affected family members from one family (You 2016). Al l of these individuals were compound heterozygous. This variant has also been re ported in ClinVar (Variation ID: 236225). This variant has been identified in 0. 06% (19/33748) of Latino chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs202020308). Although this variant has been seen in the general population, its frequency is low enough to be consiste nt with a recessive carrier frequency. Computational prediction tools and conser vation analysis suggest that the p.Cys367Phe variant may impact the protein, tho ugh this information is not predictive enough to determine pathogenicity. Functi onal studies provide some evidence that the p.Cys367Phe variant may impact prote in function (You 2016). However, these types of assays may not accurately repres ent biological function. In summary, while there is some suspicion for a pathoge nic role, the clinical significance of the p.Cys367Phe variant is uncertain. ACM G/AMP Criteria applied: PP1; PP3; PS3_Supporting, PM1_Supporting, PM3_Supporting -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.51

BayesDel_addAF

Benign

-0.0044

BayesDel_noAF

Uncertain

0.11

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.46

Eigen

Uncertain

0.51

Eigen_PC

Uncertain

0.44

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Benign

0.85

M_CAP

Benign

0.058

MetaRNN

Uncertain

0.56

MetaSVM

Benign

-0.91

MutationAssessor

Uncertain

2.7

PhyloP100

7.9

PrimateAI

Uncertain

0.60

PROVEAN

Pathogenic

-5.0

REVEL

Uncertain

0.37

Sift

Uncertain

0.0020

Sift4G

Uncertain

0.0040

Polyphen

1.0

Vest4

0.93

MVP

0.68

MPC

0.68

ClinPred

0.80

GERP RS

5.0

Varity_R

0.81

gMVP

0.55

Mutation Taster

=64/36

disease causing (ClinVar)

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over