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rs184422577

chr14-24240300-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_001099274.3(TINF2):c.1092G>A(p.Leu364=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00471 in 1,613,966 control chromosomes in the GnomAD database, including 84 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0042 ( 11 hom., cov: 32)
Exomes 𝑓: 0.0048 ( 73 hom. )

Consequence

TINF2
NM_001099274.3 synonymous

Scores

2

Clinical Significance

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

Conservation

PhyloP100: -0.275
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]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4
?
    BP4 - Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc.)
Computational evidence support a benign effect (BayesDel_noAF=-0.6).
BP6
?
    BP6 - Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation
Variant 14-24240300-C-T is Benign according to our data. Variant chr14-24240300-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 312947.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-24240300-C-T is described in Lovd as [Likely_benign].
BP7
?
    BP7 - A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved
Synonymous conserved (PhyloP=-0.275 with no splicing effect.
BS1
?
    BS1 - Allele frequency is greater than expected for disorder
Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00423 (643/152150) while in subpopulation SAS AF= 0.00539 (26/4824). AF 95% confidence interval is 0.00382. There are 11 homozygotes in gnomad4. There are 303 alleles in male gnomad4 subpopulation. This position pass quality control queck.
BS2
?
    BS2 - Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age
High AC in GnomAd at 644 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
TINF2NM_001099274.3 linkuse as main transcriptc.1092G>A p.Leu364= synonymous_variant 7/9 ENST00000267415.12

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
TINF2ENST00000267415.12 linkuse as main transcriptc.1092G>A p.Leu364= synonymous_variant 7/91 NM_001099274.3 P1Q9BSI4-1

Frequencies

GnomAD3 genomes
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.00424
AC:
644
AN:
152032
Hom.:
11
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.000749
Gnomad AMI
AF:
0.0186
Gnomad AMR
AF:
0.00216
Gnomad ASJ
AF:
0.0648
Gnomad EAS
AF:
0.000193
Gnomad SAS
AF:
0.00539
Gnomad FIN
AF:
0.000661
Gnomad MID
AF:
0.0127
Gnomad NFE
AF:
0.00422
Gnomad OTH
AF:
0.00621
GnomAD3 exomes
AF:
0.00558
AC:
1393
AN:
249520
Hom.:
21
AF XY:
0.00566
AC XY:
766
AN XY:
135380
show subpopulations
Gnomad AFR exome
AF:
0.000904
Gnomad AMR exome
AF:
0.00267
Gnomad ASJ exome
AF:
0.0582
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00435
Gnomad FIN exome
AF:
0.000883
Gnomad NFE exome
AF:
0.00440
Gnomad OTH exome
AF:
0.00825
GnomAD4 exome
AF:
0.00476
AC:
6961
AN:
1461816
Hom.:
73
Cov.:
32
AF XY:
0.00482
AC XY:
3504
AN XY:
727210
show subpopulations
Gnomad4 AFR exome
AF:
0.000717
Gnomad4 AMR exome
AF:
0.00253
Gnomad4 ASJ exome
AF:
0.0598
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00422
Gnomad4 FIN exome
AF:
0.000993
Gnomad4 NFE exome
AF:
0.00391
Gnomad4 OTH exome
AF:
0.00770
GnomAD4 genome
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.00423
AC:
643
AN:
152150
Hom.:
11
Cov.:
32
AF XY:
0.00407
AC XY:
303
AN XY:
74380
show subpopulations
Gnomad4 AFR
AF:
0.000723
Gnomad4 AMR
AF:
0.00216
Gnomad4 ASJ
AF:
0.0648
Gnomad4 EAS
AF:
0.000193
Gnomad4 SAS
AF:
0.00539
Gnomad4 FIN
AF:
0.000661
Gnomad4 NFE
AF:
0.00422
Gnomad4 OTH
AF:
0.00615
Alfa
AF:
0.00766
Hom.:
7
Bravo
AF:
0.00404
Asia WGS
AF:
0.00318
AC:
11
AN:
3478
EpiCase
AF:
0.00420
EpiControl
AF:
0.00616

ClinVar

Significance: Benign/Likely benign
Submissions summary: Benign:9
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Benign:4
Likely benign, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenJun 01, 2023TINF2: BP4, BP7, BS2 -
Likely benign, no assertion criteria providedclinical testingLaboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)-- -
Benign, criteria provided, single submitterclinical testingGeneDxMay 23, 2019- -
Likely benign, no assertion criteria providedclinical testingClinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center-- -
not specified Benign:1
Benign, criteria provided, single submitterclinical testingGenetic Services Laboratory, University of ChicagoSep 27, 2018- -
Dyskeratosis congenita, autosomal dominant 3 Benign:1
Benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 12, 2018This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Revesz syndrome Benign:1
Benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 12, 2018This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Dyskeratosis congenita Benign:1
Benign, criteria provided, single submitterclinical testingInvitaeJan 29, 2024- -
TINF2-related disorder Benign:1
Benign, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact SciencesApr 18, 2019This variant is classified as 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
BayesDel_noAF
Benign
-0.60
Cadd
Benign
1.4
Dann
Benign
0.73
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.16
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.

Other links and lift over

dbSNP: rs184422577; hg19: chr14-24709506; API