16-1500444-G-A

Variant names:

• chr16-1500444-G-A
• rs202020308
• NM_016111.4:c.1100G>A

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PM5 PP3_Moderate

The NM_016111.4(TELO2):​c.1100G>A​(p.Cys367Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C367F) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: TELO2 NM_016111.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.94
• Publications: 0 publications found

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), G2P, ClinGen, Orphanet, PanelApp Australia

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr16-1500444-G-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 236225.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.905

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_016111.4. 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
	TELO2	NM_016111.4	MANE Select	c.1100G>A	p.Cys367Tyr	missense	Exon 8 of 21	NP_057195.2	Q9Y4R8
	TELO2	NM_001351846.2		c.1100G>A	p.Cys367Tyr	missense	Exon 8 of 21	NP_001338775.1	Q9Y4R8

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TELO2	ENST00000262319.11	TSL:1 MANE Select	c.1100G>A	p.Cys367Tyr	missense	Exon 8 of 21	ENSP00000262319.6	Q9Y4R8
	TELO2	ENST00000889741.1		c.1241G>A	p.Cys414Tyr	missense	Exon 8 of 21	ENSP00000559800.1
	TELO2	ENST00000914530.1		c.1241G>A	p.Cys414Tyr	missense	Exon 8 of 21	ENSP00000584589.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1457534 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 724868

African (AFR) AF: 0.00 AC: 0 AN: 33460

American (AMR) AF: 0.00 AC: 0 AN: 44302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25944

East Asian (EAS) AF: 0.00 AC: 0 AN: 39538

South Asian (SAS) AF: 0.00 AC: 0 AN: 85662

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51710

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5684

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111072

Other (OTH) AF: 0.00 AC: 0 AN: 60162

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.85
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.14
CADD	Uncertain	25
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.64	D
Eigen	Uncertain	0.50
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.87	D
M_CAP	Benign	0.050	D
MetaRNN	Pathogenic	0.91	D
MetaSVM	Benign	-0.90	T
MutationAssessor	Uncertain	2.7	M
PhyloP100		7.9
PrimateAI	Uncertain	0.68	T
PROVEAN	Pathogenic	-5.1	D
REVEL	Uncertain	0.41
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0040	D
Polyphen		1.0	D
Vest4		0.92
MutPred		0.64		Loss of catalytic residue at L368 (P = 0.0419)
MVP		0.67
MPC		0.72
ClinPred		0.99	D
GERP RS		5.0
Varity_R		0.77
gMVP		0.60
Mutation Taster		=58/42	polymorphism

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: rs202020308; hg19: chr16-1550445;