14-24241104-G-C

Position:

• chr14-24241104-G-C

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4 BS2

The NM_001099274.3(TINF2):​c.520C>G​(p.Leu174Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000616 in 1,461,892 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000062 (0 hom.)
• Consequence: TINF2 NM_001099274.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.717

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 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.27681822).
• BS2: High AC in GnomAdExome4 at 9 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TINF2	NM_001099274.3	c.520C>G	p.Leu174Val	missense_variant	5/9	ENST00000267415.12	NP_001092744.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TINF2	ENST00000267415.12	c.520C>G	p.Leu174Val	missense_variant	5/9	1	NM_001099274.3	ENSP00000267415.7

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000120 AC: 3 AN: 249588 Hom.: 0 AF XY: 0.0000148 AC XY: 2 AN XY: 135410

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000556

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000177

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000616 AC: 9 AN: 1461892 Hom.: 0 Cov.: 32 AF XY: 0.00000688 AC XY: 5 AN XY: 727246

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000719

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000826 AC: 1

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.040
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.071	T;.;T;.;.;T
Eigen	Benign	-0.0095
Eigen_PC	Benign	-0.048
FATHMM_MKL	Benign	0.51	D
M_CAP	Uncertain	0.19	D
MetaRNN	Benign	0.28	T;T;T;T;T;T
MetaSVM	Uncertain	0.069	D
MutationAssessor	Benign	2.0	M;M;M;.;.;.
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-0.45	.;N;N;.;.;D
REVEL	Uncertain	0.45
Sift	Benign	0.24	.;T;T;.;.;T
Sift4G	Pathogenic	0.0	.;D;D;.;.;.
Polyphen		1.0	D;.;D;D;.;.
Vest4		0.28, 0.29
MutPred		0.35		Gain of catalytic residue at V173 (P = 0.001);Gain of catalytic residue at V173 (P = 0.001);Gain of catalytic residue at V173 (P = 0.001);.;.;.;
MVP		0.86
MPC		0.43
ClinPred		0.71	D
GERP RS		2.3
Varity_R		0.31
gMVP		0.11

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.19		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: rs374116388; hg19: chr14-24710310;