16-75627905-G-C

Position:

chr16-75627905-G-C

Variant summary

Our verdict is Benign. Variant got -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. 12/20 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

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 links:

KARS1 (HGNC:):

KARS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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. Variant chr16-75627905-G-C is described in Lovd as [Benign].

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/exons	MANE	Protein	UniProt
KARS1	NM_005548.3 linkuse as main transcript	c.1784C>G	p.Thr595Ser	missense_variant	14/14	ENST00000302445.8	NP_005539.1	Q15046-1
KARS1	NM_001130089.2 linkuse as main transcript	c.1868C>G	p.Thr623Ser	missense_variant	15/15		NP_001123561.1	Q15046-2
KARS1	NM_001378148.1 linkuse as main transcript	c.1316C>G	p.Thr439Ser	missense_variant	14/14		NP_001365077.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KARS1	ENST00000302445.8 linkuse as main transcript	c.1784C>G	p.Thr595Ser	missense_variant	14/14	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

GnomAD3 exomes

AF:

0.0584

AC:

14678

AN:

251416

Hom.:

1176

AF XY:

0.0539

AC XY:

7318

AN XY:

135896

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 SAS exome

AF:

0.0532

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

Gnomad4 AFR exome

AF:

0.330

Gnomad4 AMR exome

AF:

0.0290

Gnomad4 ASJ exome

AF:

0.0414

Gnomad4 EAS exome

AF:

0.00539

Gnomad4 SAS exome

AF:

0.0520

Gnomad4 FIN exome

AF:

0.0677

Gnomad4 NFE exome

AF:

0.0386

Gnomad4 OTH exome

AF:

0.0603

GnomAD4 genome

AF:

0.120

AC:

18201

AN:

152246

Hom.:

2288

Cov.:

AF XY:

0.116

AC XY:

8656

AN XY:

74444

show subpopulations

Gnomad4 AFR

AF:

0.322

Gnomad4 AMR

AF:

0.0498

Gnomad4 ASJ

AF:

0.0421

Gnomad4 EAS

AF:

0.00501

Gnomad4 SAS

AF:

0.0545

Gnomad4 FIN

AF:

0.0644

Gnomad4 NFE

AF:

0.0405

Gnomad4 OTH

AF:

0.0819

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

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 24, 2014	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). -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 09, 2017	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

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -

Autosomal recessive nonsyndromic hearing loss 89

Benign:1

Benign, criteria provided, single submitter

clinical testing

Mendelics

May 28, 2019

- -

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

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

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

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over