Genetic Variant TERF2IP:p.Asp6His (chr16-75647898-G-C) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

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

The NM_018975.4(TERF2IP):c.16G>C(p.Asp6His) variant causes a missense change. The variant allele was found at a frequency of 0.000000687 in 1,454,696 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D6N) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

TERF2IP
NM_018975.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 4.21

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:

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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=0.22890192).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TERF2IP	NM_018975.4 link	c.16G>C	p.Asp6His	missense_variant	Exon 1 of 3	ENST00000300086.5	NP_061848.2	Q9NYB0
KARS1	NM_005548.3 link	c.-259C>G		upstream_gene_variant		ENST00000302445.8	NP_005539.1	Q15046-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TERF2IP	ENST00000300086.5 link	c.16G>C	p.Asp6His	missense_variant	Exon 1 of 3	1	NM_018975.4	ENSP00000300086.4		Q9NYB0
KARS1	ENST00000302445.8 link	c.-259C>G		upstream_gene_variant		1	NM_005548.3	ENSP00000303043.3		Q15046-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.87e-7

AC:

AN:

1454696

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

722358

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33256

American (AMR)

AF:

0.00

AC:

AN:

44264

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25948

East Asian (EAS)

AF:

0.00

AC:

AN:

39492

South Asian (SAS)

AF:

0.00

AC:

AN:

86042

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53224

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5740

European-Non Finnish (NFE)

AF:

9.04e-7

AC:

AN:

1106760

Other (OTH)

AF:

0.00

AC:

AN:

59970

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.61

BayesDel_addAF

Benign

-0.12

BayesDel_noAF

Benign

-0.41

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.12

Eigen

Benign

0.091

Eigen_PC

Benign

0.16

FATHMM_MKL

Uncertain

0.79

LIST_S2

Benign

0.78

M_CAP

Uncertain

0.12

MetaRNN

Benign

0.23

MetaSVM

Benign

-0.73

MutationAssessor

Uncertain

2.0

PhyloP100

4.2

PrimateAI

Uncertain

0.58

PROVEAN

Benign

-0.98

REVEL

Benign

0.17

Sift

Uncertain

0.0030

Sift4G

Uncertain

0.0040

Polyphen

0.38

Vest4

0.21

MutPred

0.49

Gain of methylation at K9 (P = 0.059);

MVP

0.67

MPC

1.8

ClinPred

0.89

GERP RS

4.8

PromoterAI

-0.078

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.8

Varity_R

0.35

gMVP

0.54

Mutation Taster

=97/3

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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16-75647898-G-C

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over