rs142777869

Positions:

chr14-24240746-G-T

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_ModerateBP6_Very_StrongBS1BS2

The NM_001099274.3(TINF2):c.734C>A(p.Ser245Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000813 in 1,613,488 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.00047 ( 1 hom., cov: 32)

Exomes 𝑓: 0.00085 ( 7 hom. )

Consequence

TINF2
NM_001099274.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9O:1

Conservation

PhyloP100: -0.0950

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -18 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.08085504).

BP6

Variant 14-24240746-G-T is Benign according to our data. Variant chr14-24240746-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 38916.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-24240746-G-T is described in Lovd as [Pathogenic]. Variant chr14-24240746-G-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000473 (72/152314) while in subpopulation SAS AF= 0.00331 (16/4830). AF 95% confidence interval is 0.00208. There are 1 homozygotes in gnomad4. There are 37 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 72 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TINF2	NM_001099274.3 linkuse as main transcript	c.734C>A	p.Ser245Tyr	missense_variant	6/9	ENST00000267415.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TINF2	ENST00000267415.12 linkuse as main transcript	c.734C>A	p.Ser245Tyr	missense_variant	6/9	1	NM_001099274.3	P1	Q9BSI4-1

Frequencies

GnomAD3 genomes

AF:

0.000473

AC:

AN:

152196

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000965

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000262

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00331

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.000603

Gnomad OTH

AF:

0.00144

GnomAD3 exomes

AF:

0.00112

AC:

278

AN:

248018

Hom.:

AF XY:

0.00138

AC XY:

186

AN XY:

134612

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000610

Gnomad ASJ exome

AF:

0.000600

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00514

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000722

Gnomad OTH exome

AF:

0.00216

GnomAD4 exome

AF:

0.000848

AC:

1239

AN:

1461174

Hom.:

Cov.:

AF XY:

0.00102

AC XY:

745

AN XY:

726878

show subpopulations

Gnomad4 AFR exome

AF:

0.0000899

Gnomad4 AMR exome

AF:

0.000583

Gnomad4 ASJ exome

AF:

0.000689

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00528

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000550

Gnomad4 OTH exome

AF:

0.00109

GnomAD4 genome

AF:

0.000473

AC:

AN:

152314

Hom.:

Cov.:

AF XY:

0.000497

AC XY:

AN XY:

74486

show subpopulations

Gnomad4 AFR

AF:

0.0000962

Gnomad4 AMR

AF:

0.000261

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00331

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000603

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.000631

Hom.:

Bravo

AF:

0.000385

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000481

AC:

ExAC

AF:

0.00121

AC:

147

Asia WGS

AF:

0.00289

AC:

AN:

3478

EpiCase

AF:

0.00125

EpiControl

AF:

0.00113

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Oct 22, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital	Dec 29, 2019	- -

Dyskeratosis congenita

Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 22, 2024	- -
Benign, criteria provided, single submitter	curation	Sema4, Sema4	Mar 26, 2020	- -

Revesz syndrome;C3151445:Dyskeratosis congenita, autosomal dominant 3;C4551974:Dyskeratosis congenita, autosomal dominant 1

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

May 13, 2022

- -

not provided

Benign:1

Likely benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

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). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Malignant tumor of breast

Benign:1

Benign, no assertion criteria provided

clinical testing

Center of Medical Genetics and Primary Health Care

- -

Revesz syndrome

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. -

Dyskeratosis congenita, autosomal dominant 1

Other:1

not provided, no classification provided

literature only

GeneReviews

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.18

BayesDel_noAF

Uncertain

-0.030

CADD

Benign

DANN

Benign

0.96

DEOGEN2

Benign

0.19

T;.;T;.;.;T

Eigen

Benign

-0.40

Eigen_PC

Benign

-0.43

FATHMM_MKL

Benign

0.075

M_CAP

Uncertain

0.088

MetaRNN

Benign

0.081

T;T;T;T;T;T

MetaSVM

Benign

-0.62

MutationAssessor

Benign

0.69

N;N;N;.;.;.

MutationTaster

Benign

8.2e-12

A;A;A;A;A;A

PrimateAI

Benign

0.35

PROVEAN

Benign

-1.9

.;N;N;.;.;D

REVEL

Uncertain

0.58

Sift

Uncertain

0.0030

.;D;D;.;.;D

Sift4G

Uncertain

0.012

.;D;D;.;.;.

Polyphen

0.91

P;.;P;P;.;.

Vest4

0.35, 0.70

MVP

0.75

MPC

0.44

ClinPred

0.047

GERP RS

0.99

Varity_R

0.087

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