16-75647922-C-T

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_018975.4(TERF2IP):c.40C>T(p.Pro14Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,459,218 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 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. P14H) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

TERF2IP
NM_018975.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.00

Publications

0 publications found

Variant links:

Genes affected

TERF2IP (HGNC:19246): (TERF2 interacting protein) Enables G-rich strand telomeric DNA binding activity and phosphatase binding activity. Involved in several processes, including positive regulation of NIK/NF-kappaB signaling; regulation of nucleobase-containing compound metabolic process; and regulation of protein modification process. Located in chromosome, telomeric region; cytosol; and nuclear body. Part of shelterin complex. [provided by Alliance of Genome Resources, Apr 2022]

TERF2IP links:

KARS1 (HGNC:6215): (lysyl-tRNA synthetase 1) Aminoacyl-tRNA synthetases are a class of enzymes that charge tRNAs with their cognate amino acids. Lysyl-tRNA synthetase is a homodimer localized to the cytoplasm which belongs to the class II family of tRNA synthetases. It has been shown to be a target of autoantibodies in the human autoimmune diseases, polymyositis or dermatomyositis. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

KARS1 Gene-Disease associations (from GenCC):

autosomal recessive nonsyndromic hearing loss 89
Inheritance: AR Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), G2P
leukoencephalopathy, progressive, infantile-onset, with or without deafness
Inheritance: AR Classification: STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
Charcot-Marie-Tooth disease recessive intermediate B
Inheritance: AR, Unknown Classification: SUPPORTIVE, LIMITED Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)
hearing loss, autosomal recessive
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
nonsyndromic genetic hearing loss
Inheritance: AR Classification: LIMITED Submitted by: ClinGen

KARS1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.0870547).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TERF2IP	NM_018975.4 link	c.40C>T	p.Pro14Ser	missense_variant	Exon 1 of 3	ENST00000300086.5	NP_061848.2	Q9NYB0
TERF2IP	XM_047434216.1 link	c.40C>T	p.Pro14Ser	missense_variant	Exon 1 of 2		XP_047290172.1
TERF2IP	NR_144545.2 link	n.150C>T		non_coding_transcript_exon_variant	Exon 1 of 3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
TERF2IP	ENST00000300086.5 link	c.40C>T	p.Pro14Ser	missense_variant	Exon 1 of 3	1	NM_018975.4	ENSP00000300086.4	Q9NYB0
KARS1	ENST00000566560.5 link	n.176+546G>A		intron_variant	Intron 1 of 6	1
TERF2IP	ENST00000653858.1 link	c.40C>T	p.Pro14Ser	missense_variant	Exon 1 of 4			ENSP00000499565.1	A0A590UJT3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.0000160

AC:

AN:

249932

AF XY:

0.00000739

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000164

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000274

AC:

AN:

1459218

Hom.:

Cov.:

AF XY:

0.00000276

AC XY:

AN XY:

725508

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33414

American (AMR)

AF:

0.00

AC:

AN:

44538

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26060

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39620

South Asian (SAS)

AF:

0.0000348

AC:

AN:

86182

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53242

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5758

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1110168

Other (OTH)

AF:

0.00

AC:

AN:

60236

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.412

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ExAC

AF:

0.0000247

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Oct 17, 2023

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.40C>T (p.P14S) alteration is located in exon 1 (coding exon 1) of the TERF2IP gene. This alteration results from a C to T substitution at nucleotide position 40, causing the proline (P) at amino acid position 14 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.31

BayesDel_addAF

Benign

-0.42

BayesDel_noAF

Benign

-0.58

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.055

Eigen

Benign

-0.19

Eigen_PC

Benign

-0.0087

FATHMM_MKL

Benign

0.19

LIST_S2

Benign

0.67

M_CAP

Benign

0.013

MetaRNN

Benign

0.087

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.4

PhyloP100

2.0

PrimateAI

Benign

0.46

PROVEAN

Benign

-0.93

REVEL

Benign

0.027

Sift

Benign

0.45

Sift4G

Benign

0.68

Polyphen

0.29

Vest4

0.14

MutPred

0.33

Gain of phosphorylation at P14 (P = 0.0626);

MVP

0.52

MPC

0.90

ClinPred

0.15

GERP RS

4.8

PromoterAI

-0.035

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.6

Varity_R

0.096

gMVP

0.46

Mutation Taster

=93/7

polymorphism

(source)

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

Publications

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16-75647922-C-T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over