chr16-75627905-G-C

Variant names:

Variant summary

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

The NM_005548.3(KARS1):c.1784C>G(p.Thr595Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0539 in 1,578,048 control chromosomes in the GnomAD database, including 5,488 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.12 ( 2288 hom., cov: 33)

Exomes 𝑓: 0.047 ( 3200 hom. )

Consequence

KARS1
NM_005548.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 6.42

Publications

18 publications found

Variant links:

Genes affected

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 (MetaRNN=0.003862083).

BP6

Variant 16-75627905-G-C is Benign according to our data. Variant chr16-75627905-G-C is described in ClinVar as [Benign]. Clinvar id is 226682.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.317 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KARS1	NM_005548.3 link	c.1784C>G	p.Thr595Ser	missense_variant	Exon 14 of 14	ENST00000302445.8	NP_005539.1	Q15046-1
KARS1	NM_001130089.2 link	c.1868C>G	p.Thr623Ser	missense_variant	Exon 15 of 15		NP_001123561.1	Q15046-2
KARS1	NM_001378148.1 link	c.1316C>G	p.Thr439Ser	missense_variant	Exon 14 of 14		NP_001365077.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KARS1	ENST00000302445.8 link	c.1784C>G	p.Thr595Ser	missense_variant	Exon 14 of 14	1	NM_005548.3	ENSP00000303043.3		Q15046-1

Frequencies

GnomAD3 genomes

AF:

0.119

AC:

18163

AN:

152128

Hom.:

2283

Cov.:

show subpopulations

Gnomad AFR

AF:

0.322

Gnomad AMI

AF:

0.0219

Gnomad AMR

AF:

0.0499

Gnomad ASJ

AF:

0.0421

Gnomad EAS

AF:

0.00519

Gnomad SAS

AF:

0.0547

Gnomad FIN

AF:

0.0644

Gnomad MID

AF:

0.0348

Gnomad NFE

AF:

0.0405

Gnomad OTH

AF:

0.0828

GnomAD2 exomes

AF:

0.0584

AC:

14678

AN:

251416

AF XY:

0.0539

show subpopulations

Gnomad AFR exome

AF:

0.328

Gnomad AMR exome

AF:

0.0265

Gnomad ASJ exome

AF:

0.0392

Gnomad EAS exome

AF:

0.00511

Gnomad FIN exome

AF:

0.0652

Gnomad NFE exome

AF:

0.0405

Gnomad OTH exome

AF:

0.0482

GnomAD4 exome

AF:

0.0468

AC:

66796

AN:

1425802

Hom.:

3200

Cov.:

AF XY:

0.0460

AC XY:

32736

AN XY:

711752

show subpopulations

African (AFR)

AF:

0.330

AC:

10633

AN:

32228

American (AMR)

AF:

0.0290

AC:

1297

AN:

44694

Ashkenazi Jewish (ASJ)

AF:

0.0414

AC:

1073

AN:

25918

East Asian (EAS)

AF:

0.00539

AC:

213

AN:

39534

South Asian (SAS)

AF:

0.0520

AC:

4442

AN:

85484

European-Finnish (FIN)

AF:

0.0677

AC:

3615

AN:

53390

Middle Eastern (MID)

AF:

0.0471

AC:

267

AN:

5664

European-Non Finnish (NFE)

AF:

0.0386

AC:

41691

AN:

1079722

Other (OTH)

AF:

0.0603

AC:

3565

AN:

59168

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.459

Heterozygous variant carriers

2755

5510

8265

11020

13775

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.120

AC:

18201

AN:

152246

Hom.:

2288

Cov.:

AF XY:

0.116

AC XY:

8656

AN XY:

74444

show subpopulations

African (AFR)

AF:

0.322

AC:

13360

AN:

41500

American (AMR)

AF:

0.0498

AC:

762

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.0421

AC:

146

AN:

3472

East Asian (EAS)

AF:

0.00501

AC:

AN:

5194

South Asian (SAS)

AF:

0.0545

AC:

263

AN:

4824

European-Finnish (FIN)

AF:

0.0644

AC:

683

AN:

10604

Middle Eastern (MID)

AF:

0.0374

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0405

AC:

2757

AN:

68036

Other (OTH)

AF:

0.0819

AC:

173

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

733

1466

2199

2932

3665

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0430

Hom.:

109

Bravo

AF:

0.127

TwinsUK

AF:

0.0334

AC:

124

ALSPAC

AF:

0.0415

AC:

160

ESP6500AA

AF:

0.324

AC:

1426

ESP6500EA

AF:

0.0405

AC:

348

ExAC

AF:

0.0657

AC:

7980

Asia WGS

AF:

0.0550

AC:

191

AN:

3478

EpiCase

AF:

0.0399

EpiControl

AF:

0.0351

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Nov 24, 2014

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Thr623Ser in exon 15 of KARS: This variant is not expected to have clinical sign ificance because it has been identified in 32.4% (1426/4396) of African American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http ://evs.gs.washington.edu/EVS; dbSNP rs6834). -

May 09, 2017

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

not provided

Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

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

- -

Autosomal recessive nonsyndromic hearing loss 89

Benign:1

May 28, 2019

Mendelics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.071

BayesDel_addAF

Benign

-0.52

BayesDel_noAF

Benign

-0.38

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.16

.;T

Eigen

Benign

-0.20

Eigen_PC

Benign

0.057

FATHMM_MKL

Uncertain

0.96

LIST_S2

Benign

0.51

T;T

MetaRNN

Benign

0.0039

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.55

.;N

PhyloP100

6.4

PrimateAI

Benign

0.37

PROVEAN

Benign

-0.11

N;N

REVEL

Uncertain

0.31

Sift

Benign

0.18

T;T

Sift4G

Benign

0.079

T;T

Polyphen

0.021

B;B

Vest4

0.090

MutPred

0.046

.;Loss of glycosylation at T595 (P = 0.049);

MPC

0.084

ClinPred

0.016

GERP RS

5.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.056

gMVP

0.66

Mutation Taster

=96/4

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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chr16-75627905-G-C

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