NM_001099274.3:c.1334G>A

Variant names:

• chr14-24239819-C-T
• rs2040525483
• NM_001099274.3:c.1334G>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001099274.3(TINF2):​c.1334G>A​(p.Arg445Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,132 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R445G) has been classified as Uncertain significance.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
• Consequence: TINF2 NM_001099274.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -3.00
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• dyskeratosis congenita, autosomal dominant 3

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, G2P, ClinGen, PanelApp Australia, Labcorp Genetics (formerly Invitae)
• Revesz syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, G2P, PanelApp Australia
• pulmonary fibrosis

  Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
• dyskeratosis congenita

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Hoyeraal-Hreidarsson syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• thyroid gland papillary carcinoma

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.04139483).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001099274.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TINF2	NM_001099274.3	MANE Select	c.1334G>A	p.Arg445Lys	missense	Exon 9 of 9	NP_001092744.1	Q9BSI4-1
	TINF2	NM_001363668.2		c.1229G>A	p.Arg410Lys	missense	Exon 8 of 8	NP_001350597.1	B4DFJ1
	TINF2	NM_012461.3		c.*596G>A		3_prime_UTR	Exon 6 of 6	NP_036593.2	Q9BSI4-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TINF2	ENST00000267415.12	TSL:1 MANE Select	c.1334G>A	p.Arg445Lys	missense	Exon 9 of 9	ENSP00000267415.7	Q9BSI4-1
	TINF2	ENST00000399423.8	TSL:1	c.*596G>A		3_prime_UTR	Exon 6 of 6	ENSP00000382350.4	Q9BSI4-2
	TINF2	ENST00000943625.1		c.1280G>A	p.Arg427Lys	missense	Exon 9 of 9	ENSP00000613684.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152132 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: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 32

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152132 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74304

African (AFR) AF: 0.0000241 AC: 1 AN: 41432

American (AMR) AF: 0.00 AC: 0 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5204

South Asian (SAS) AF: 0.00 AC: 0 AN: 4816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10598

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68026

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Dyskeratosis congenita (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.092
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	0.0080
DANN	Benign	0.62
DEOGEN2	Benign	0.028	T
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.9
FATHMM_MKL	Benign	0.041	N
M_CAP	Benign	0.047	D
MetaRNN	Benign	0.041	T
MetaSVM	Benign	-0.70	T
MutationAssessor	Benign	0.90	L
PhyloP100		-3.0
PrimateAI	Benign	0.24	T
PROVEAN	Benign	0.27	N
REVEL	Benign	0.15
Sift	Benign	0.80	T
Sift4G	Benign	0.73	T
Polyphen		0.068	B
Vest4		0.048
MutPred		0.23		Gain of ubiquitination at R445 (P = 0.0037)
MVP		0.51
MPC		0.23
ClinPred		0.065	T
GERP RS		-9.6
Varity_R		0.043
gMVP		0.21
Mutation Taster		=99/1	polymorphism

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

Other links and lift over

dbSNP: rs2040525483; hg19: chr14-24709025;