rs144863771

chr16-1494313-C-A

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS1

The NM_016111.4(TELO2):c.32C>A(p.Ala11Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00112 in 1,613,398 control chromosomes in the GnomAD database, including 12 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A11N) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00094 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0011 (12 hom.)
• Consequence: TELO2 NM_016111.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: 0.505

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 Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0067305863).
• BP6: Variant 16-1494313-C-A is Benign according to our data. Variant chr16-1494313-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 376945.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=1}.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000939 (143/152256) while in subpopulation NFE AF= 0.00113 (77/68022). AF 95% confidence interval is 0.000928. There are 0 homozygotes in gnomad4. There are 63 alleles in male gnomad4 subpopulation. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TELO2	NM_016111.4	c.32C>A	p.Ala11Asp	missense_variant	2/21	ENST00000262319.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TELO2	ENST00000262319.11	c.32C>A	p.Ala11Asp	missense_variant	2/21	1	NM_016111.4	P1
TELO2	ENST00000497339.6	c.32C>A	p.Ala11Asp	missense_variant, NMD_transcript_variant	2/12	5

Frequencies

GnomAD3 genomes AF: 0.000940 AC: 143 AN: 152138 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000983

Gnomad ASJ AF: 0.0112

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.000377

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00113

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00137 AC: 343 AN: 250980 Hom.: 1 AF XY: 0.00144 AC XY: 195 AN XY: 135768

Gnomad AFR exome AF: 0.0000616

Gnomad AMR exome AF: 0.000896

Gnomad ASJ exome AF: 0.0127

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000653

Gnomad FIN exome AF: 0.000279

Gnomad NFE exome AF: 0.00123

Gnomad OTH exome AF: 0.00278

GnomAD4 exome AF: 0.00114 AC: 1670 AN: 1461142 Hom.: 12 Cov.: 33 AF XY: 0.00117 AC XY: 852 AN XY: 726860

Gnomad4 AFR exome AF: 0.0000896

Gnomad4 AMR exome AF: 0.000939

Gnomad4 ASJ exome AF: 0.0139

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000812

Gnomad4 FIN exome AF: 0.000227

Gnomad4 NFE exome AF: 0.000937

Gnomad4 OTH exome AF: 0.00192

GnomAD4 genome AF: 0.000939 AC: 143 AN: 152256 Hom.: 0 Cov.: 32 AF XY: 0.000846 AC XY: 63 AN XY: 74452

Gnomad4 AFR AF: 0.0000963

Gnomad4 AMR AF: 0.000981

Gnomad4 ASJ AF: 0.0112

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.000377

Gnomad4 NFE AF: 0.00113

Gnomad4 OTH AF: 0.00

Alfa AF: 0.00138 Hom.: 0

Bravo AF: 0.00113

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00105 AC: 9

ExAC AF: 0.00115 AC: 140

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00218

EpiControl AF: 0.00190

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jan 18, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Dec 31, 2019	- -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 01, 2021

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.61
Cadd	Benign	8.0
Dann	Benign	0.78
DEOGEN2	Benign	0.12	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.23	N
LIST_S2	Benign	0.61	T
M_CAP	Benign	0.0078	T
MetaRNN	Benign	0.0067	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	1.8	L
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.012
Sift	Benign	0.030	D
Sift4G	Benign	0.081	T
Polyphen		0.026	B
Vest4		0.39
MVP		0.19
MPC		0.20
ClinPred		0.014	T
GERP RS		2.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.097
gMVP		0.32

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs144863771; hg19: chr16-1544314;