NM_001099274.3:c.1166T>C

Variant names:

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_001099274.3(TINF2):c.1166T>C(p.Ile389Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000756 in 1,613,968 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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. I389K) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00028 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000054 ( 0 hom. )

Consequence

TINF2
NM_001099274.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:2

Conservation

PhyloP100: 2.90

Publications

3 publications found

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 Gene-Disease associations (from GenCC):

dyskeratosis congenita, autosomal dominant 3
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, G2P, ClinGen, PanelApp Australia, Labcorp Genetics (formerly Invitae)
Revesz syndrome
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, G2P, PanelApp Australia
pulmonary fibrosis
Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
dyskeratosis congenita
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
Hoyeraal-Hreidarsson syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
thyroid gland papillary carcinoma
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

TINF2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.05637157).

BS2

High AC in GnomAd4 at 43 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001099274.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TINF2	NM_001099274.3	MANE Select	c.1166T>C	p.Ile389Thr	missense	Exon 8 of 9	NP_001092744.1	Q9BSI4-1
TINF2	NM_001363668.2		c.1061T>C	p.Ile354Thr	missense	Exon 7 of 8	NP_001350597.1	B4DFJ1
TINF2	NM_012461.3		c.*296T>C		3_prime_UTR	Exon 6 of 6	NP_036593.2	Q9BSI4-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TINF2	ENST00000267415.12	TSL:1 MANE Select	c.1166T>C	p.Ile389Thr	missense	Exon 8 of 9	ENSP00000267415.7	Q9BSI4-1
TINF2	ENST00000399423.8	TSL:1	c.*296T>C		3_prime_UTR	Exon 6 of 6	ENSP00000382350.4	Q9BSI4-2
TINF2	ENST00000943625.1		c.1112T>C	p.Ile371Thr	missense	Exon 8 of 9	ENSP00000613684.1

Frequencies

GnomAD3 genomes

AF:

0.000283

AC:

AN:

151962

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000992

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000386

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000128

AC:

AN:

249542

AF XY:

0.0000960

show subpopulations

Gnomad AFR exome

AF:

0.00155

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000445

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000540

AC:

AN:

1461888

Hom.:

Cov.:

AF XY:

0.0000468

AC XY:

AN XY:

727242

show subpopulations

African (AFR)

AF:

0.00128

AC:

AN:

33480

American (AMR)

AF:

0.0000224

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.000277

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000232

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53416

Middle Eastern (MID)

AF:

0.000173

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000117

AC:

AN:

1112010

Other (OTH)

AF:

0.000132

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000283

AC:

AN:

152080

Hom.:

Cov.:

AF XY:

0.000256

AC XY:

AN XY:

74362

show subpopulations

African (AFR)

AF:

0.000989

AC:

AN:

41468

American (AMR)

AF:

0.00

AC:

AN:

15264

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.000387

AC:

AN:

5166

South Asian (SAS)

AF:

0.00

AC:

AN:

4812

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10600

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67984

Other (OTH)

AF:

0.00

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.468

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000133

Hom.:

Bravo

AF:

0.000321

ESP6500AA

AF:

0.000758

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000165

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Dyskeratosis congenita (2)

not specified (2)

not provided (1)

TINF2-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.18

BayesDel_addAF

Benign

-0.088

BayesDel_noAF

Uncertain

0.070

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.20

Eigen

Uncertain

0.51

Eigen_PC

Uncertain

0.52

FATHMM_MKL

Uncertain

0.90

M_CAP

Uncertain

0.21

MetaRNN

Benign

0.056

MetaSVM

Uncertain

0.46

MutationAssessor

Benign

1.9

PhyloP100

2.9

PrimateAI

Uncertain

0.60

PROVEAN

Pathogenic

-4.6

REVEL

Pathogenic

0.67

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

0.99

Vest4

0.49

MVP

0.88

MPC

0.35

ClinPred

0.18

GERP RS

5.4

PromoterAI

0.030

Neutral

(source)

Varity_R

0.32

gMVP

0.39

Mutation Taster

=60/40

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over