rs189265179

Variant names:

• chr14-24241715-T-C
• rs189265179
• NM_001099274.3:c.359A>G

Your query was ambiguous. Multiple possible variants found:

• chr14-24241715-T-C
• chr14-24241715-T-A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001099274.3(TINF2):​c.359A>G​(p.Gln120Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000978 in 1,613,242 control chromosomes in the GnomAD database, including 32 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. Q120Q) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0018 (5 hom., cov: 32)
  • Exomes 𝑓: 0.00089 (27 hom.)
• Consequence: TINF2 NM_001099274.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 1.26
• Publications: 4 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.005641818).
• BP6: Variant 14-24241715-T-C is Benign according to our data. Variant chr14-24241715-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 312955.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population amr. GnomAdExome4 allele frequency = 0.000894 (1306/1460910) while in subpopulation AMR AF = 0.0279 (1245/44638). AF 95% confidence interval is 0.0266. There are 27 homozygotes in GnomAdExome4. There are 564 alleles in the male GnomAdExome4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 271 AD gene.

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.359A>G	p.Gln120Arg	missense	Exon 3 of 9	NP_001092744.1	Q9BSI4-1
	TINF2	NM_001363668.2		c.254A>G	p.Gln85Arg	missense	Exon 2 of 8	NP_001350597.1	B4DFJ1
	TINF2	NM_012461.3		c.359A>G	p.Gln120Arg	missense	Exon 3 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.359A>G	p.Gln120Arg	missense	Exon 3 of 9	ENSP00000267415.7	Q9BSI4-1
	TINF2	ENST00000399423.8	TSL:1	c.359A>G	p.Gln120Arg	missense	Exon 3 of 6	ENSP00000382350.4	Q9BSI4-2
	TINF2	ENST00000943625.1		c.359A>G	p.Gln120Arg	missense	Exon 3 of 9	ENSP00000613684.1

Frequencies

GnomAD3 genomes AF: 0.00175 AC: 266 AN: 152216 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.000338

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0161

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: 0.0000441

Gnomad OTH AF: 0.00144

GnomAD2 exomes AF: 0.00395 AC: 980 AN: 247810 AF XY: 0.00306

Gnomad AFR exome AF: 0.000329

Gnomad AMR exome AF: 0.0278

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000178

Gnomad OTH exome AF: 0.00315

GnomAD4 exome AF: 0.000894 AC: 1306 AN: 1460910 Hom.: 27 Cov.: 32 AF XY: 0.000776 AC XY: 564 AN XY: 726576

African (AFR) AF: 0.000299 AC: 10 AN: 33470

American (AMR) AF: 0.0279 AC: 1245 AN: 44638

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26082

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 85942

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53380

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.0000144 AC: 16 AN: 1111570

Other (OTH) AF: 0.000580 AC: 35 AN: 60362

GnomAD4 genome AF: 0.00178 AC: 271 AN: 152332 Hom.: 5 Cov.: 32 AF XY: 0.00196 AC XY: 146 AN XY: 74486

African (AFR) AF: 0.000337 AC: 14 AN: 41574

American (AMR) AF: 0.0164 AC: 251 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68028

Other (OTH) AF: 0.00142 AC: 3 AN: 2112

Alfa AF: 0.000419 Hom.: 0

Bravo AF: 0.00285

ESP6500AA AF: 0.000268 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00291 AC: 352

Asia WGS AF: 0.00173 AC: 6 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Dyskeratosis congenita (1)
-	-	1	Dyskeratosis congenita, autosomal dominant 3 (1)
-	-	1	Revesz syndrome (1)
-	-	1	Revesz syndrome;C3151445:Dyskeratosis congenita, autosomal dominant 3;C4551974:Dyskeratosis congenita, autosomal dominant 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	15
DANN	Benign	0.94
DEOGEN2	Benign	0.076	T
Eigen	Benign	-0.47
Eigen_PC	Benign	-0.41
FATHMM_MKL	Benign	0.62	D
MetaRNN	Benign	0.0056	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.8	L
PhyloP100		1.3
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.018
Sift	Benign	0.12	T
Sift4G	Benign	0.10	T
Polyphen		0.10	B
Vest4		0.23
MVP		0.40
MPC		0.24
ClinPred		0.0098	T
GERP RS		1.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.12
gMVP		0.075
Mutation Taster		=297/3	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: rs189265179; hg19: chr14-24710921;