rs117234138

Positions:

• chr14-24239917-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001099274.3(TINF2):​c.1236C>T​(p.Asn412=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00487 in 1,614,208 control chromosomes in the GnomAD database, including 44 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0036 (4 hom., cov: 32)
  • Exomes 𝑓: 0.0050 (40 hom.)
• Consequence: TINF2 NM_001099274.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 1.15

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]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.6).
• BP6: Variant 14-24239917-G-A is Benign according to our data. Variant chr14-24239917-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 238288.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.15 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00355 (541/152318) while in subpopulation SAS AF= 0.0116 (56/4822). AF 95% confidence interval is 0.00918. There are 4 homozygotes in gnomad4. There are 265 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 541 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TINF2	NM_001099274.3	c.1236C>T	p.Asn412=	synonymous_variant	9/9	ENST00000267415.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TINF2	ENST00000267415.12	c.1236C>T	p.Asn412=	synonymous_variant	9/9	1	NM_001099274.3	P1

Frequencies

GnomAD3 genomes AF: 0.00355 AC: 541 AN: 152200 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.00121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00183

Gnomad ASJ AF: 0.00576

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.0116

Gnomad FIN AF: 0.000941

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00541

Gnomad OTH AF: 0.00334

GnomAD3 exomes AF: 0.00470 AC: 1172 AN: 249564 Hom.: 10 AF XY: 0.00518 AC XY: 701 AN XY: 135408

Gnomad AFR exome AF: 0.00110

Gnomad AMR exome AF: 0.00301

Gnomad ASJ exome AF: 0.00914

Gnomad EAS exome AF: 0.0000556

Gnomad SAS exome AF: 0.0112

Gnomad FIN exome AF: 0.00111

Gnomad NFE exome AF: 0.00482

Gnomad OTH exome AF: 0.00726

GnomAD4 exome AF: 0.00500 AC: 7315 AN: 1461890 Hom.: 40 Cov.: 32 AF XY: 0.00530 AC XY: 3858 AN XY: 727246

Gnomad4 AFR exome AF: 0.000747

Gnomad4 AMR exome AF: 0.00302

Gnomad4 ASJ exome AF: 0.0103

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0112

Gnomad4 FIN exome AF: 0.00122

Gnomad4 NFE exome AF: 0.00501

Gnomad4 OTH exome AF: 0.00432

GnomAD4 genome AF: 0.00355 AC: 541 AN: 152318 Hom.: 4 Cov.: 32 AF XY: 0.00356 AC XY: 265 AN XY: 74470

Gnomad4 AFR AF: 0.00120

Gnomad4 AMR AF: 0.00183

Gnomad4 ASJ AF: 0.00576

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.0116

Gnomad4 FIN AF: 0.000941

Gnomad4 NFE AF: 0.00541

Gnomad4 OTH AF: 0.00331

Alfa AF: 0.00482 Hom.: 1

Bravo AF: 0.00325

Asia WGS AF: 0.00404 AC: 15 AN: 3478

EpiCase AF: 0.00540

EpiControl AF: 0.00409

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	May 07, 2021	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	TINF2: BP4, BP7, BS1, BS2 -

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 19, 2022

- -

Dyskeratosis congenita, autosomal dominant 3 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This 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 submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This 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 submitter

clinical testing

Invitae

Jan 31, 2024

- -

TINF2-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 29, 2019

This 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	5.8
DANN	Benign	0.77

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs117234138; hg19: chr14-24709123;