16-1500444-G-T

Position:

chr16-1500444-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP5

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 Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00017 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00018 ( 0 hom. )

Consequence

TELO2
NM_016111.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:10U:1

Conservation

PhyloP100: 7.94

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 16-1500444-G-T is Pathogenic according to our data. Variant chr16-1500444-G-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 236225.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Pathogenic=4, Likely_pathogenic=4}. Variant chr16-1500444-G-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TELO2	NM_016111.4 linkuse as main transcript	c.1100G>T	p.Cys367Phe	missense_variant	8/21	ENST00000262319.11	NP_057195.2	Q9Y4R8B4DXS2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TELO2	ENST00000262319.11 linkuse as main transcript	c.1100G>T	p.Cys367Phe	missense_variant	8/21	1	NM_016111.4	ENSP00000262319.6		Q9Y4R8
TELO2	ENST00000497339.6 linkuse as main transcript	n.1100G>T		non_coding_transcript_exon_variant	8/12	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

GnomAD3 exomes

AF:

0.000177

AC:

AN:

237468

Hom.:

AF XY:

0.000162

AC XY:

AN XY:

129556

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 SAS 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

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.000497

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000213

Gnomad4 OTH exome

AF:

0.0000831

GnomAD4 genome

AF:

0.000171

AC:

AN:

152376

Hom.:

Cov.:

AF XY:

0.000215

AC XY:

AN XY:

74508

show subpopulations

Gnomad4 AFR

AF:

0.0000240

Gnomad4 AMR

AF:

0.000588

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000235

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000156

Hom.:

Bravo

AF:

0.000162

ExAC

AF:

0.000149

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:10Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

TELO2-related intellectual disability-neurodevelopmental disorder

Pathogenic:8

Likely pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 31, 2018	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Dec 31, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Jul 16, 2023	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 -
Pathogenic, no assertion criteria provided	literature only	OMIM	Sep 10, 2019	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	DASA	Feb 05, 2022	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. -
Pathogenic, criteria provided, single submitter	research	Baylor-Hopkins Center for Mendelian Genomics, Johns Hopkins University School of Medicine	-	- -
Likely pathogenic, criteria provided, single submitter	research	UNC Molecular Genetics Laboratory, University of North Carolina at Chapel Hill	-	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). -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 28, 2024	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. -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 14, 2024

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). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on TELO2 protein function. For these reasons, this variant has been classified as Pathogenic. -

TELO2-related disorder

Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 29, 2024

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

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Apr 12, 2018

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

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

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

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over