rs552794694

chr14-24240737-G-A

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_001099274.3(TINF2):c.743C>T(p.Thr248Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000583 in 1,613,368 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.000059 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000058 (1 hom.)
• Consequence: TINF2 NM_001099274.3 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.245

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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.040091276).
• BP6: Variant 14-24240737-G-A is Benign according to our data. Variant chr14-24240737-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 529172.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd at 9 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TINF2	NM_001099274.3	c.743C>T	p.Thr248Met	missense_variant	6/9	ENST00000267415.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TINF2	ENST00000267415.12	c.743C>T	p.Thr248Met	missense_variant	6/9	1	NM_001099274.3	P1

Frequencies

GnomAD3 genomes AF: 0.0000592 AC: 9 AN: 152148 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.000283

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000129 AC: 32 AN: 248224 Hom.: 1 AF XY: 0.000119 AC XY: 16 AN XY: 134700

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000111

Gnomad SAS exome AF: 0.000294

Gnomad FIN exome AF: 0.000975

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000582 AC: 85 AN: 1461220 Hom.: 1 Cov.: 32 AF XY: 0.0000619 AC XY: 45 AN XY: 726896

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.000348

Gnomad4 FIN exome AF: 0.000656

Gnomad4 NFE exome AF: 0.00000720

Gnomad4 OTH exome AF: 0.000166

GnomAD4 genome AF: 0.0000592 AC: 9 AN: 152148 Hom.: 0 Cov.: 32 AF XY: 0.0000807 AC XY: 6 AN XY: 74316

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.000621

Gnomad4 FIN AF: 0.000283

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000151

ExAC AF: 0.0000496 AC: 6

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Dyskeratosis congenita Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.28
Cadd	Benign	18
Dann	Uncertain	1.0
DEOGEN2	Benign	0.060	T;.;T;.;.;T
Eigen	Benign	-0.62
Eigen_PC	Benign	-0.71
FATHMM_MKL	Benign	0.052	N
M_CAP	Uncertain	0.21	D
MetaRNN	Benign	0.040	T;T;T;T;T;T
MetaSVM	Benign	-0.53	T
MutationAssessor	Benign	0.90	L;L;L;.;.;.
MutationTaster	Benign	1.0	N;N;N;N;N;N
PrimateAI	Benign	0.35	T
Polyphen		0.99	D;.;D;D;.;.
Vest4		0.15, 0.16
MutPred		0.19		Gain of catalytic residue at R247 (P = 0);Gain of catalytic residue at R247 (P = 0);Gain of catalytic residue at R247 (P = 0);.;.;.;
MVP		0.72
MPC		0.65
ClinPred		0.098	T
GERP RS		1.4
Varity_R		0.027
gMVP		0.14

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: rs552794694; hg19: chr14-24709943;