16-75647845-C-G

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.-38C>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.161 in 1,594,648 control chromosomes in the GnomAD database, including 40,157 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.27 ( 8396 hom., cov: 33)

Exomes 𝑓: 0.15 ( 31761 hom. )

Consequence

TERF2IP
NM_018975.4 5_prime_UTR

Scores

Clinical Significance

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

Conservation

PhyloP100: -2.82

Publications

20 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=-0.8).

BP6

Variant 16-75647845-C-G is Benign according to our data. Variant chr16-75647845-C-G is described in ClinVar as [Benign]. Clinvar id is 1232920.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.707 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TERF2IP	NM_018975.4 link	c.-38C>G		5_prime_UTR_variant	Exon 1 of 3	ENST00000300086.5	NP_061848.2	Q9NYB0
KARS1	NM_005548.3 link	c.-206G>C		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.-38C>G		5_prime_UTR_variant	Exon 1 of 3	1	NM_018975.4	ENSP00000300086.4		Q9NYB0
KARS1	ENST00000302445.8 link	c.-206G>C		upstream_gene_variant		1	NM_005548.3	ENSP00000303043.3		Q15046-1

Frequencies

GnomAD3 genomes

AF:

0.265

AC:

40306

AN:

152028

Hom.:

8372

Cov.:

show subpopulations

Gnomad AFR

AF:

0.500

Gnomad AMI

AF:

0.128

Gnomad AMR

AF:

0.350

Gnomad ASJ

AF:

0.178

Gnomad EAS

AF:

0.727

Gnomad SAS

AF:

0.352

Gnomad FIN

AF:

0.123

Gnomad MID

AF:

0.0955

Gnomad NFE

AF:

0.0920

Gnomad OTH

AF:

0.230

GnomAD2 exomes

AF:

0.257

AC:

61141

AN:

238124

AF XY:

0.242

show subpopulations

Gnomad AFR exome

AF:

0.509

Gnomad AMR exome

AF:

0.457

Gnomad ASJ exome

AF:

0.158

Gnomad EAS exome

AF:

0.763

Gnomad FIN exome

AF:

0.125

Gnomad NFE exome

AF:

0.0940

Gnomad OTH exome

AF:

0.194

GnomAD4 exome

AF:

0.150

AC:

216915

AN:

1442502

Hom.:

31761

Cov.:

AF XY:

0.152

AC XY:

109036

AN XY:

715390

show subpopulations

African (AFR)

AF:

0.510

AC:

16732

AN:

32812

American (AMR)

AF:

0.442

AC:

18846

AN:

42594

Ashkenazi Jewish (ASJ)

AF:

0.159

AC:

4000

AN:

25086

East Asian (EAS)

AF:

0.752

AC:

29593

AN:

39376

South Asian (SAS)

AF:

0.318

AC:

27020

AN:

84836

European-Finnish (FIN)

AF:

0.126

AC:

6636

AN:

52496

Middle Eastern (MID)

AF:

0.140

AC:

785

AN:

5612

European-Non Finnish (NFE)

AF:

0.0927

AC:

102044

AN:

1100390

Other (OTH)

AF:

0.190

AC:

11259

AN:

59300

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

9531

19062

28592

38123

47654

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.265

AC:

40392

AN:

152146

Hom.:

8396

Cov.:

AF XY:

0.273

AC XY:

20289

AN XY:

74386

show subpopulations

African (AFR)

AF:

0.500

AC:

20771

AN:

41528

American (AMR)

AF:

0.351

AC:

5376

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.178

AC:

618

AN:

3470

East Asian (EAS)

AF:

0.727

AC:

3735

AN:

5138

South Asian (SAS)

AF:

0.351

AC:

1695

AN:

4826

European-Finnish (FIN)

AF:

0.123

AC:

1306

AN:

10592

Middle Eastern (MID)

AF:

0.103

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0920

AC:

6254

AN:

67978

Other (OTH)

AF:

0.232

AC:

490

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1240

2480

3719

4959

6199

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.101

Hom.:

280

Bravo

AF:

0.296

Asia WGS

AF:

0.508

AC:

1763

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

Jun 14, 2019

GeneDx

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

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.80

CADD

Benign

0.057

(source)

DANN

Benign

0.37

PhyloP100

-2.8

PromoterAI

0.023

Neutral

(source)

Mutation Taster

=300/0

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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16-75647845-C-G

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