rs144274136

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1PM2BP4_Moderate

The NM_005548.3(KARS1):c.1485A>G(p.Ile495Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00063 in 1,614,200 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00031 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00066 ( 1 hom. )

Consequence

KARS1
NM_005548.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:7B:1

Conservation

PhyloP100: -0.519

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_005548.3

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.13859332).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
KARS1	NM_005548.3 linkuse as main transcript	c.1485A>G	p.Ile495Met	missense_variant	12/14	ENST00000302445.8
KARS1	NM_001130089.2 linkuse as main transcript	c.1569A>G	p.Ile523Met	missense_variant	13/15
KARS1	NM_001378148.1 linkuse as main transcript	c.1017A>G	p.Ile339Met	missense_variant	12/14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KARS1	ENST00000302445.8 linkuse as main transcript	c.1485A>G	p.Ile495Met	missense_variant	12/14	1	NM_005548.3	A1	Q15046-1
KARS1	ENST00000319410.9 linkuse as main transcript	c.1569A>G	p.Ile523Met	missense_variant	13/15	1		P4	Q15046-2
KARS1	ENST00000568378.5 linkuse as main transcript	c.147-1492A>G		intron_variant		5
KARS1	ENST00000564578.5 linkuse as main transcript	c.*1028A>G		3_prime_UTR_variant, NMD_transcript_variant	12/14	5

Frequencies

GnomAD3 genomes

AF:

0.000315

AC:

AN:

152272

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000964

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000188

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000603

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000513

AC:

129

AN:

251468

Hom.:

AF XY:

0.000530

AC XY:

AN XY:

135910

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.0000992

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000139

Gnomad NFE exome

AF:

0.00108

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000663

AC:

969

AN:

1461810

Hom.:

Cov.:

AF XY:

0.000672

AC XY:

489

AN XY:

727216

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.0000671

Gnomad4 ASJ exome

AF:

0.000153

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000348

Gnomad4 FIN exome

AF:

0.000169

Gnomad4 NFE exome

AF:

0.000838

Gnomad4 OTH exome

AF:

0.000282

GnomAD4 genome

AF:

0.000315

AC:

AN:

152390

Hom.:

Cov.:

AF XY:

0.000295

AC XY:

AN XY:

74518

show subpopulations

Gnomad4 AFR

AF:

0.0000961

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000188

Gnomad4 NFE

AF:

0.000603

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.000785

Hom.:

Bravo

AF:

0.000355

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.00104

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000465

AC:

ExAC

AF:

0.000692

AC:

EpiCase

AF:

0.00104

EpiControl

AF:

0.000889

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:7Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:4Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Athena Diagnostics	May 06, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Oct 01, 2022	This sequence change replaces isoleucine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 523 of the KARS protein (p.Ile523Met). This variant is present in population databases (rs144274136, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with KARS-related conditions. ClinVar contains an entry for this variant (Variation ID: 228757). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt KARS protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 06, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Nov 19, 2020	- -

not specified

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Dec 20, 2022	The c.1569A>G (p.I523M) alteration is located in exon 13 (coding exon 12) of the KARS gene. This alteration results from a A to G substitution at nucleotide position 1569, causing the isoleucine (I) at amino acid position 523 to be replaced by a methionine (M). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -
Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jul 17, 2015	Variant classified as Uncertain Significance - Favor Benign. The p.Ile523Met var iant in KARS has not been previously reported in individuals with hearing loss, but has been identified in 0.12% (79/66738) of European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs144274136 ). Computational prediction tools and conservation analysis do not provide stro ng support for or against an impact to the protein. In summary, while the clinic al significance of the p.Ile523Met variant is uncertain, its frequency in the ge neral population suggests that it is more likely to be benign. -

Hearing impairment

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Department of Otolaryngology – Head & Neck Surgery, Cochlear Implant Center

Apr 12, 2021

PP3_Supporting -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.32

BayesDel_addAF

Benign

-0.12

BayesDel_noAF

Uncertain

0.0

Cadd

Benign

Dann

Uncertain

0.99

Eigen

Benign

-0.36

Eigen_PC

Benign

-0.45

FATHMM_MKL

Benign

0.48

LIST_S2

Pathogenic

0.98

D;D

M_CAP

Uncertain

0.14

MetaRNN

Benign

0.14

T;T

MetaSVM

Uncertain

0.19

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Uncertain

0.51

PROVEAN

Uncertain

-2.5

N;N

REVEL

Pathogenic

0.67

Sift

Uncertain

0.0010

D;D

Sift4G

Uncertain

0.039

D;T

Polyphen

0.0020

B;P

Vest4

0.57

MVP

0.64

MPC

0.41

ClinPred

0.12

GERP RS

-3.3

Varity_R

0.87

gMVP

0.88

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