16-75647801-G-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_018975.4(TERF2IP):c.-82G>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0215 in 1,591,968 control chromosomes in the GnomAD database, including 641 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.031 ( 111 hom., cov: 33)

Exomes 𝑓: 0.020 ( 530 hom. )

Consequence

TERF2IP
NM_018975.4 5_prime_UTR

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.666

Publications

5 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: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.79).

BP6

Variant 16-75647801-G-T is Benign according to our data. Variant chr16-75647801-G-T is described in ClinVar as [Benign]. Clinvar id is 1252803.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0612 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TERF2IP	NM_018975.4 link	c.-82G>T		5_prime_UTR_variant	Exon 1 of 3	ENST00000300086.5	NP_061848.2	Q9NYB0
KARS1	NM_005548.3 link	c.-162C>A		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.-82G>T		5_prime_UTR_variant	Exon 1 of 3	1	NM_018975.4	ENSP00000300086.4		Q9NYB0
KARS1	ENST00000302445.8 link	c.-162C>A		upstream_gene_variant		1	NM_005548.3	ENSP00000303043.3		Q15046-1

Frequencies

GnomAD3 genomes

AF:

0.0311

AC:

4733

AN:

152226

Hom.:

111

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0633

Gnomad AMI

AF:

0.0373

Gnomad AMR

AF:

0.0186

Gnomad ASJ

AF:

0.0314

Gnomad EAS

AF:

0.0288

Gnomad SAS

AF:

0.0577

Gnomad FIN

AF:

0.00593

Gnomad MID

AF:

0.0601

Gnomad NFE

AF:

0.0163

Gnomad OTH

AF:

0.0306

GnomAD4 exome

AF:

0.0205

AC:

29496

AN:

1439624

Hom.:

530

Cov.:

AF XY:

0.0219

AC XY:

15668

AN XY:

715856

show subpopulations

African (AFR)

AF:

0.0674

AC:

2213

AN:

32850

American (AMR)

AF:

0.0154

AC:

670

AN:

43620

Ashkenazi Jewish (ASJ)

AF:

0.0315

AC:

809

AN:

25674

East Asian (EAS)

AF:

0.0255

AC:

1004

AN:

39400

South Asian (SAS)

AF:

0.0656

AC:

5605

AN:

85402

European-Finnish (FIN)

AF:

0.00601

AC:

316

AN:

52572

Middle Eastern (MID)

AF:

0.0498

AC:

272

AN:

5464

European-Non Finnish (NFE)

AF:

0.0156

AC:

17099

AN:

1095154

Other (OTH)

AF:

0.0253

AC:

1508

AN:

59488

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

1606

3212

4819

6425

8031

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0311

AC:

4736

AN:

152344

Hom.:

111

Cov.:

AF XY:

0.0309

AC XY:

2303

AN XY:

74494

show subpopulations

African (AFR)

AF:

0.0633

AC:

2630

AN:

41578

American (AMR)

AF:

0.0186

AC:

285

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.0314

AC:

109

AN:

3470

East Asian (EAS)

AF:

0.0288

AC:

149

AN:

5170

South Asian (SAS)

AF:

0.0571

AC:

276

AN:

4832

European-Finnish (FIN)

AF:

0.00593

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.0612

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0163

AC:

1108

AN:

68038

Other (OTH)

AF:

0.0302

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

232

464

696

928

1160

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0221

Hom.:

Bravo

AF:

0.0329

Asia WGS

AF:

0.0640

AC:

220

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Jun 15, 2019

GeneDx

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

-0.79

CADD

Benign

6.4

(source)

DANN

Benign

0.72

PhyloP100

0.67

PromoterAI

-0.019

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Mutation Taster

=298/2

polymorphism (auto)

(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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16-75647801-G-T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over