rs202093758

Positions:

chr14-24242259-C-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001099274.3(TINF2):c.74G>C(p.Gly25Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00155 in 1,614,070 control chromosomes in the GnomAD database, including 5 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 Likely benign (★★).

Frequency

Genomes: 𝑓 0.0016 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0015 ( 4 hom. )

Consequence

TINF2
NM_001099274.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: -0.295

Variant links:

Genes affected

TINF2 (HGNC:11824): (TERF1 interacting nuclear factor 2) This gene encodes one of the proteins of the shelterin, or telosome, complex which protects telomeres by allowing the cell to distinguish between telomeres and regions of DNA damage. The protein encoded by this gene is a critical part of shelterin; it interacts with the three DNA-binding proteins of the shelterin complex, and it is important for assembly of the complex. Mutations in this gene cause dyskeratosis congenita (DKC), an inherited bone marrow failure syndrome. [provided by RefSeq, Mar 2010]

TINF2 links:

TINF2 (HGNC:):

TINF2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0077293515).

BP6

Variant 14-24242259-C-G is Benign according to our data. Variant chr14-24242259-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 312956.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-24242259-C-G is described in Lovd as [Benign]. Variant chr14-24242259-C-G is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00158 (241/152254) while in subpopulation NFE AF= 0.00229 (156/68034). AF 95% confidence interval is 0.002. There are 1 homozygotes in gnomad4. There are 120 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 241 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TINF2	NM_001099274.3 linkuse as main transcript	c.74G>C	p.Gly25Ala	missense_variant	1/9	ENST00000267415.12	NP_001092744.1	Q9BSI4-1
TINF2	NM_001363668.2 linkuse as main transcript	c.74G>C	p.Gly25Ala	missense_variant	1/8		NP_001350597.1
TINF2	NM_012461.3 linkuse as main transcript	c.74G>C	p.Gly25Ala	missense_variant	1/6		NP_036593.2	Q9BSI4-2
TINF2	XM_011536642.3 linkuse as main transcript	c.74G>C	p.Gly25Ala	missense_variant	1/5		XP_011534944.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TINF2	ENST00000267415.12 linkuse as main transcript	c.74G>C	p.Gly25Ala	missense_variant	1/9	1	NM_001099274.3	ENSP00000267415.7		Q9BSI4-1

Frequencies

GnomAD3 genomes

AF:

0.00158

AC:

241

AN:

152254

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00173

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00678

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00229

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.00175

AC:

436

AN:

248512

Hom.:

AF XY:

0.00165

AC XY:

223

AN XY:

135132

show subpopulations

Gnomad AFR exome

AF:

0.000131

Gnomad AMR exome

AF:

0.000174

Gnomad ASJ exome

AF:

0.00189

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00635

Gnomad NFE exome

AF:

0.00235

Gnomad OTH exome

AF:

0.00132

GnomAD4 exome

AF:

0.00155

AC:

2263

AN:

1461816

Hom.:

Cov.:

AF XY:

0.00157

AC XY:

1140

AN XY:

727204

show subpopulations

Gnomad4 AFR exome

AF:

0.000119

Gnomad4 AMR exome

AF:

0.000179

Gnomad4 ASJ exome

AF:

0.00119

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00634

Gnomad4 NFE exome

AF:

0.00161

Gnomad4 OTH exome

AF:

0.00154

GnomAD4 genome

AF:

0.00158

AC:

241

AN:

152254

Hom.:

Cov.:

AF XY:

0.00161

AC XY:

120

AN XY:

74380

show subpopulations

Gnomad4 AFR

AF:

0.000121

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00173

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00678

Gnomad4 NFE

AF:

0.00229

Gnomad4 OTH

AF:

0.000478

Alfa

AF:

0.00244

Hom.:

Bravo

AF:

0.000948

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.00130

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00180

AC:

ExAC

AF:

0.00190

AC:

230

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00142

EpiControl

AF:

0.000889

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2023	TINF2: BP4, BS1 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 07, 2019	- -
Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Dyskeratosis congenita

Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 24, 2024	- -
Benign, criteria provided, single submitter	curation	Sema4, Sema4	Oct 14, 2021	- -

not specified

Benign:1

Benign, no assertion criteria provided

clinical testing

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

- -

Dyskeratosis congenita, autosomal dominant 3

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Revesz syndrome

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

TINF2-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 09, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.53

BayesDel_noAF

Benign

-0.53

CADD

Benign

1.0

DANN

Benign

0.65

DEOGEN2

Benign

0.064

T;.;T;.;.;.;T;T

Eigen

Benign

-0.86

Eigen_PC

Benign

-0.90

FATHMM_MKL

Benign

0.16

M_CAP

Benign

0.013

MetaRNN

Benign

0.0077

T;T;T;T;T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.9

M;M;M;.;.;.;.;.

PrimateAI

Benign

0.46

PROVEAN

Benign

-0.020

.;N;N;.;.;N;N;N

REVEL

Benign

0.010

Sift

Benign

0.27

.;T;T;.;.;T;T;T

Sift4G

Benign

0.84

.;T;T;.;T;T;T;T

Polyphen

0.24

B;B;B;B;.;.;.;.

Vest4

0.099, 0.10, 0.10, 0.11, 0.12

MVP

0.30

MPC

2.1

ClinPred

0.010

GERP RS

2.6

Varity_R

0.058

gMVP

0.19

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