rs17102311

chr14-24240759-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001099274.3(TINF2):c.721C>T(p.Pro241Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00122 in 1,613,606 control chromosomes in the GnomAD database, including 21 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. P241P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0064 (9 hom., cov: 32)
  • Exomes 𝑓: 0.00068 (12 hom.)
• Consequence: TINF2 NM_001099274.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 1.48

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0050059557).
• BP6: Variant 14-24240759-G-A is Benign according to our data. Variant chr14-24240759-G-A is described in ClinVar as [Benign]. Clinvar id is 413988.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0064 (974/152294) while in subpopulation AFR AF= 0.0224 (929/41558). AF 95% confidence interval is 0.0212. There are 9 homozygotes in gnomad4. There are 445 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 962 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TINF2	NM_001099274.3	c.721C>T	p.Pro241Ser	missense_variant	6/9	ENST00000267415.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TINF2	ENST00000267415.12	c.721C>T	p.Pro241Ser	missense_variant	6/9	1	NM_001099274.3	P1

Frequencies

GnomAD3 genomes AF: 0.00632 AC: 962 AN: 152176 Hom.: 9 Cov.: 32

Gnomad AFR AF: 0.0221

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00209

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00432

GnomAD3 exomes AF: 0.00165 AC: 409 AN: 247808 Hom.: 5 AF XY: 0.00112 AC XY: 151 AN XY: 134574

Gnomad AFR exome AF: 0.0237

Gnomad AMR exome AF: 0.000902

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000982

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000625

Gnomad OTH exome AF: 0.000499

GnomAD4 exome AF: 0.000675 AC: 987 AN: 1461312 Hom.: 12 Cov.: 32 AF XY: 0.000552 AC XY: 401 AN XY: 726938

Gnomad4 AFR exome AF: 0.0234

Gnomad4 AMR exome AF: 0.00103

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000225

Gnomad4 OTH exome AF: 0.00189

GnomAD4 genome AF: 0.00640 AC: 974 AN: 152294 Hom.: 9 Cov.: 32 AF XY: 0.00598 AC XY: 445 AN XY: 74466

Gnomad4 AFR AF: 0.0224

Gnomad4 AMR AF: 0.00209

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.00428

Alfa AF: 0.00320 Hom.: 3

Bravo AF: 0.00738

ESP6500AA AF: 0.0241 AC: 96

ESP6500EA AF: 0.000120 AC: 1

ExAC AF: 0.00216 AC: 261

Asia WGS AF: 0.00260 AC: 9 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Nov 11, 2020

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Dec 06, 2019

In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 21199492, 30964210) -

Dyskeratosis congenita Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 23, 2024

- -

TINF2-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 02, 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
AlphaMissense	Benign	0.089
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.15
Cadd	Benign	18
Dann	Uncertain	1.0
DEOGEN2	Benign	0.095	T;.;T;.;.;T
Eigen	Uncertain	0.21
Eigen_PC	Benign	0.10
FATHMM_MKL	Benign	0.63	D
MetaRNN	Benign	0.0050	T;T;T;T;T;T
MetaSVM	Uncertain	0.20	D
MutationAssessor	Benign	2.0	M;M;M;.;.;.
MutationTaster	Benign	1.0	D;D;N;N;N;N
PrimateAI	Benign	0.31	T
Polyphen		1.0	D;.;D;D;.;.
Vest4		0.060, 0.076
MVP		0.89
MPC		0.58
ClinPred		0.030	T
GERP RS		3.5
Varity_R		0.10
gMVP		0.23

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

Other links and lift over

dbSNP: rs17102311; hg19: chr14-24709965;