rs17102313

Variant names:

• chr14-24240770-C-T
• rs17102313
• NM_001099274.3:c.710G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001099274.3(TINF2):​c.710G>A​(p.Gly237Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00641 in 1,613,564 control chromosomes in the GnomAD database, including 604 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. G237G) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.034 (310 hom., cov: 32)
  • Exomes 𝑓: 0.0035 (294 hom.)
• Consequence: TINF2 NM_001099274.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.398
• Publications: 11 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: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• Revesz syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, PanelApp Australia, Orphanet
• 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0026425421).
• BP6: Variant 14-24240770-C-T is Benign according to our data. Variant chr14-24240770-C-T is described in ClinVar as Benign. ClinVar VariationId is 312951.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.117 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TINF2	NM_001099274.3	MANE Select	c.710G>A	p.Gly237Asp	missense	Exon 6 of 9	NP_001092744.1
	TINF2	NM_001363668.2		c.605G>A	p.Gly202Asp	missense	Exon 5 of 8	NP_001350597.1
	TINF2	NM_012461.3		c.710G>A	p.Gly237Asp	missense	Exon 6 of 6	NP_036593.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TINF2	ENST00000267415.12	TSL:1 MANE Select	c.710G>A	p.Gly237Asp	missense	Exon 6 of 9	ENSP00000267415.7
	TINF2	ENST00000399423.8	TSL:1	c.710G>A	p.Gly237Asp	missense	Exon 6 of 6	ENSP00000382350.4
	TINF2	ENST00000646753.1		c.605G>A	p.Gly202Asp	missense	Exon 5 of 8	ENSP00000494065.1

Frequencies

GnomAD3 genomes AF: 0.0343 AC: 5214 AN: 152072 Hom.: 305 Cov.: 32

Gnomad AFR AF: 0.119

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0127

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00103

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000294

Gnomad OTH AF: 0.0259

GnomAD2 exomes AF: 0.00832 AC: 2061 AN: 247706 AF XY: 0.00609

Gnomad AFR exome AF: 0.119

Gnomad AMR exome AF: 0.00511

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000111

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000143

Gnomad OTH exome AF: 0.00399

GnomAD4 exome AF: 0.00349 AC: 5105 AN: 1461374 Hom.: 294 Cov.: 32 AF XY: 0.00297 AC XY: 2159 AN XY: 726992

African (AFR) AF: 0.126 AC: 4199 AN: 33400

American (AMR) AF: 0.00584 AC: 261 AN: 44662

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26106

East Asian (EAS) AF: 0.000176 AC: 7 AN: 39696

South Asian (SAS) AF: 0.000336 AC: 29 AN: 86240

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53318

Middle Eastern (MID) AF: 0.00312 AC: 18 AN: 5764

European-Non Finnish (NFE) AF: 0.0000944 AC: 105 AN: 1111832

Other (OTH) AF: 0.00804 AC: 485 AN: 60356

GnomAD4 genome AF: 0.0344 AC: 5234 AN: 152190 Hom.: 310 Cov.: 32 AF XY: 0.0332 AC XY: 2470 AN XY: 74402

African (AFR) AF: 0.120 AC: 4960 AN: 41490

American (AMR) AF: 0.0127 AC: 195 AN: 15300

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.000829 AC: 4 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10594

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000294 AC: 20 AN: 68012

Other (OTH) AF: 0.0256 AC: 54 AN: 2110

Alfa AF: 0.0131 Hom.: 182

Bravo AF: 0.0388

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.113 AC: 449

ESP6500EA AF: 0.000480 AC: 4

ExAC AF: 0.0104 AC: 1264

Asia WGS AF: 0.0180 AC: 65 AN: 3478

EpiCase AF: 0.000327

EpiControl AF: 0.000119

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Dyskeratosis congenita (2)
-	-	2	not provided (2)
-	-	1	Dyskeratosis congenita, autosomal dominant 3 (1)
-	-	1	not specified (1)
-	-	1	Revesz syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	7.7
DANN	Benign	0.89
DEOGEN2	Benign	0.089	T
Eigen	Benign	-0.66
Eigen_PC	Benign	-0.68
FATHMM_MKL	Benign	0.065	N
MetaRNN	Benign	0.0026	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.8	L
PhyloP100		0.40
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.010	N
REVEL	Benign	0.17
Sift	Benign	0.14	T
Sift4G	Benign	0.087	T
Polyphen		0.021	B
Vest4		0.070
MPC		0.24
ClinPred		0.00036	T
GERP RS		2.0
PromoterAI		-0.0016	Neutral
Varity_R		0.074
gMVP		0.21
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs17102313; hg19: chr14-24709976;