16-1500444-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP5

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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:9 U:1
• Conservation: PhyloP100: 7.94

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]

ACMG classification

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: {Likely_pathogenic=4, Pathogenic=4, Uncertain_significance=1}. Variant chr16-1500444-G-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TELO2	NM_016111.4	c.1100G>T	p.Cys367Phe	missense_variant	8/21	ENST00000262319.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TELO2	ENST00000262319.11	c.1100G>T	p.Cys367Phe	missense_variant	8/21	1	NM_016111.4	P1
TELO2	ENST00000497339.6	c.1100G>T	p.Cys367Phe	missense_variant, NMD_transcript_variant	8/12	5

Frequencies

GnomAD3 genomes AF: 0.000171 AC: 26 AN: 152258 Hom.: 0 Cov.: 33

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: 42 AN: 237468 Hom.: 0 AF XY: 0.000162 AC XY: 21 AN XY: 129556

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.: 0 Cov.: 32 AF XY: 0.000159 AC XY: 115 AN XY: 724868

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: 26 AN: 152376 Hom.: 0 Cov.: 33 AF XY: 0.000215 AC XY: 16 AN XY: 74508

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.: 0

Bravo AF: 0.000162

ExAC AF: 0.000149 AC: 18

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:9 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

TELO2-related intellectual disability-neurodevelopmental disorder Pathogenic:8

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 (0.00018 vs ND), allowing no conclusion about variant significance. c.1100G>T has been reported in the literature in multiple individuals affected with TELO2-Related Intellectual Disability-Neurodevelopmental Disorder. 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. ClinVar contains an entry for this variant (Variation ID: 236225). Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Sep 10, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Oct 19, 2020	Based on the classification scheme VCGS_Germline_v1.3.3, 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) 0802 - This variant has moderate previous evidence of pathogenicity in unrelated individuals. It has been reported as compound heterozygous with missense variants in 2 unrelated families with You-Hoover-Fong syndrome and an individual with moderate global developmental delay, microcephaly and other clinical features (PMID: 27132593 and Deciphering Developmental Disorders (DDD) Study). It has also been reported as likely pathogenic and “Uncertain Significance - Favour Pathogenic” in ClinVar. (SP) 0903 - This variant has limited evidence for segregation with disease. It segregated with syndromic intellectual disability disorder in a family with 3 affected children who are compound heterozygotes (PMID: 27132593). (SP) 1001 - This variant has strong functional evidence supporting abnormal protein function. Functional analysis using cultured fibroblasts of 2 unrelated patients showed reduced amount of TELO2 protein and its partner proteins in the TTT complex (PMID: 27132593). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
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	research	Baylor-Hopkins Center for Mendelian Genomics, Johns Hopkins University School of Medicine	-	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Dec 31, 2019	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 31, 2018	- -
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. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

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. -

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	T
BayesDel_noAF	Uncertain	0.11
Cadd	Uncertain	25
Dann	Uncertain	0.99
DEOGEN2	Uncertain	0.46	T
Eigen	Uncertain	0.51
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.85	T
M_CAP	Benign	0.058	D
MetaRNN	Uncertain	0.56	D
MetaSVM	Benign	-0.91	T
MutationAssessor	Uncertain	2.7	M
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.60	T
PROVEAN	Pathogenic	-5.0	D
REVEL	Uncertain	0.37
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0040	D
Polyphen		1.0	D
Vest4		0.93
MVP		0.68
MPC		0.68
ClinPred		0.80	D
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

Other links and lift over

dbSNP: rs202020308; hg19: chr16-1550445;