rs75124018

Variant names:

• chr14-24240709-G-A
• rs75124018
• NM_001099274.3:c.771C>T

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_001099274.3(TINF2):​c.771C>T​(p.His257His) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00133 in 1,613,880 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0010 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0014 (1 hom.)
• Consequence: TINF2 NM_001099274.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 0.370
• Publications: 1 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 -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.64).
• BP6: Variant 14-24240709-G-A is Benign according to our data. Variant chr14-24240709-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 312949.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.37 with no splicing effect.
• BS2: High AC in GnomAd4 at 155 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TINF2	NM_001099274.3	MANE Select	c.771C>T	p.His257His	synonymous	Exon 6 of 9	NP_001092744.1
	TINF2	NM_001363668.2		c.666C>T	p.His222His	synonymous	Exon 5 of 8	NP_001350597.1
	TINF2	NM_012461.3		c.771C>T	p.His257His	synonymous	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.771C>T	p.His257His	synonymous	Exon 6 of 9	ENSP00000267415.7
	TINF2	ENST00000399423.8	TSL:1	c.771C>T	p.His257His	synonymous	Exon 6 of 6	ENSP00000382350.4
	TINF2	ENST00000646753.1		c.666C>T	p.His222His	synonymous	Exon 5 of 8	ENSP00000494065.1

Frequencies

GnomAD3 genomes AF: 0.00102 AC: 155 AN: 152184 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000266

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00367

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00150

Gnomad OTH AF: 0.000479

GnomAD2 exomes AF: 0.000904 AC: 225 AN: 248854 AF XY: 0.000859

Gnomad AFR exome AF: 0.000194

Gnomad AMR exome AF: 0.000203

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00302

Gnomad NFE exome AF: 0.00128

Gnomad OTH exome AF: 0.000661

GnomAD4 exome AF: 0.00136 AC: 1995 AN: 1461578 Hom.: 1 Cov.: 32 AF XY: 0.00135 AC XY: 980 AN XY: 727088

African (AFR) AF: 0.000180 AC: 6 AN: 33418

American (AMR) AF: 0.000202 AC: 9 AN: 44660

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26122

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.000128 AC: 11 AN: 86254

European-Finnish (FIN) AF: 0.00277 AC: 148 AN: 53408

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00158 AC: 1755 AN: 1111870

Other (OTH) AF: 0.00109 AC: 66 AN: 60380

GnomAD4 genome AF: 0.00102 AC: 155 AN: 152302 Hom.: 0 Cov.: 32 AF XY: 0.00120 AC XY: 89 AN XY: 74472

African (AFR) AF: 0.000265 AC: 11 AN: 41548

American (AMR) AF: 0.000131 AC: 2 AN: 15304

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

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

European-Finnish (FIN) AF: 0.00367 AC: 39 AN: 10618

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

European-Non Finnish (NFE) AF: 0.00150 AC: 102 AN: 68030

Other (OTH) AF: 0.000474 AC: 1 AN: 2110

Alfa AF: 0.00110 Hom.: 0

Bravo AF: 0.000657

EpiCase AF: 0.000927

EpiControl AF: 0.000948

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Dyskeratosis congenita (3)
-	-	3	not specified (3)
-	-	1	Dyskeratosis congenita, autosomal dominant 3 (1)
-	-	1	not provided (1)
-	-	1	Revesz syndrome (1)
-	-	1	TINF2-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.64
CADD	Benign	5.5
DANN	Benign	0.83
PhyloP100		0.37
PromoterAI		0.048	Neutral
Mutation Taster		=98/2	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: rs75124018; hg19: chr14-24709915;