14-24240145-C-T

Variant names:

• chr14-24240145-C-T
• rs10141326
• NM_001099274.3:c.1140G>A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001099274.3(TINF2):​c.1140G>A​(p.Pro380Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0112 in 1,613,890 control chromosomes in the GnomAD database, including 1,643 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.059 (863 hom., cov: 32)
  • Exomes 𝑓: 0.0062 (780 hom.)
• Consequence: TINF2 NM_001099274.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.183

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]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.74).
• BP6: Variant 14-24240145-C-T is Benign according to our data. Variant chr14-24240145-C-T is described in ClinVar as [Benign]. Clinvar id is 312946.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.183 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.198 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TINF2	NM_001099274.3	c.1140G>A	p.Pro380Pro	synonymous_variant	Exon 8 of 9	ENST00000267415.12	NP_001092744.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TINF2	ENST00000267415.12	c.1140G>A	p.Pro380Pro	synonymous_variant	Exon 8 of 9	1	NM_001099274.3	ENSP00000267415.7

Frequencies

GnomAD3 genomes AF: 0.0589 AC: 8944 AN: 151886 Hom.: 858 Cov.: 32

Gnomad AFR AF: 0.202

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0268

Gnomad ASJ AF: 0.000867

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00125

Gnomad FIN AF: 0.0000944

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.00112

Gnomad OTH AF: 0.0459

GnomAD3 exomes AF: 0.0150 AC: 3737 AN: 249562 Hom.: 340 AF XY: 0.0112 AC XY: 1523 AN XY: 135398

Gnomad AFR exome AF: 0.204

Gnomad AMR exome AF: 0.0118

Gnomad ASJ exome AF: 0.00119

Gnomad EAS exome AF: 0.000167

Gnomad SAS exome AF: 0.000425

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000856

Gnomad OTH exome AF: 0.00874

GnomAD4 exome AF: 0.00621 AC: 9076 AN: 1461886 Hom.: 780 Cov.: 32 AF XY: 0.00535 AC XY: 3894 AN XY: 727242

Gnomad4 AFR exome AF: 0.208

Gnomad4 AMR exome AF: 0.0128

Gnomad4 ASJ exome AF: 0.00103

Gnomad4 EAS exome AF: 0.000227

Gnomad4 SAS exome AF: 0.000522

Gnomad4 FIN exome AF: 0.0000374

Gnomad4 NFE exome AF: 0.000460

Gnomad4 OTH exome AF: 0.0144

GnomAD4 genome AF: 0.0590 AC: 8970 AN: 152004 Hom.: 863 Cov.: 32 AF XY: 0.0576 AC XY: 4277 AN XY: 74286

Gnomad4 AFR AF: 0.202

Gnomad4 AMR AF: 0.0268

Gnomad4 ASJ AF: 0.000867

Gnomad4 EAS AF: 0.000194

Gnomad4 SAS AF: 0.00104

Gnomad4 FIN AF: 0.0000944

Gnomad4 NFE AF: 0.00112

Gnomad4 OTH AF: 0.0454

Alfa AF: 0.0329 Hom.: 255

Bravo AF: 0.0668

Asia WGS AF: 0.0250 AC: 86 AN: 3478

EpiCase AF: 0.00136

EpiControl AF: 0.00101

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Oct 10, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Feb 14, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Classification criteria: BA1 -

Dyskeratosis congenita, autosomal dominant 3 Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Revesz syndrome Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Dyskeratosis congenita Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
CADD	Benign	9.6
DANN	Benign	0.65

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs10141326; hg19: chr14-24709351;