rs376538590

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_005548.3(KARS1):c.1438G>C(p.Glu480Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000304 in 1,614,024 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00014 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000019 ( 0 hom. )

Consequence

KARS1
NM_005548.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 1.90

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 Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.061694145).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
KARS1	NM_005548.3 linkuse as main transcript	c.1438G>C	p.Glu480Gln	missense_variant	12/14	ENST00000302445.8
KARS1	NM_001130089.2 linkuse as main transcript	c.1522G>C	p.Glu508Gln	missense_variant	13/15
KARS1	NM_001378148.1 linkuse as main transcript	c.970G>C	p.Glu324Gln	missense_variant	12/14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KARS1	ENST00000302445.8 linkuse as main transcript	c.1438G>C	p.Glu480Gln	missense_variant	12/14	1	NM_005548.3	A1	Q15046-1
KARS1	ENST00000319410.9 linkuse as main transcript	c.1522G>C	p.Glu508Gln	missense_variant	13/15	1		P4	Q15046-2
KARS1	ENST00000568378.5 linkuse as main transcript	c.147-1539G>C		intron_variant		5
KARS1	ENST00000564578.5 linkuse as main transcript	c.*981G>C		3_prime_UTR_variant, NMD_transcript_variant	12/14	5

Frequencies

GnomAD3 genomes

AF:

0.000138

AC:

AN:

152248

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000506

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:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000398

AC:

AN:

251456

Hom.:

AF XY:

0.0000442

AC XY:

AN XY:

135900

show subpopulations

Gnomad AFR exome

AF:

0.000492

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000109

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000192

AC:

AN:

1461776

Hom.:

Cov.:

AF XY:

0.0000220

AC XY:

AN XY:

727182

show subpopulations

Gnomad4 AFR exome

AF:

0.000568

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000756

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

8.99e-7

Gnomad4 OTH exome

AF:

0.0000497

GnomAD4 genome

AF:

0.000138

AC:

AN:

152248

Hom.:

Cov.:

AF XY:

0.000161

AC XY:

AN XY:

74372

show subpopulations

Gnomad4 AFR

AF:

0.000506

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.000181

ESP6500AA

AF:

0.000455

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000494

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Jun 21, 2023	The c.1522G>C (p.E508Q) alteration is located in exon 13 (coding exon 12) of the KARS gene. This alteration results from a G to C substitution at nucleotide position 1522, causing the glutamic acid (E) at amino acid position 508 to be replaced by a glutamine (Q). 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	Mar 31, 2016	Variant classified as Uncertain Significance - Favor Benign. The p.Glu508Gln var iant in KARS has not been previously reported in individuals with hearing loss, but has been identified in 6/10390 of African chromosomes by the Exome Aggregati on Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs376538590). Althoug h this variant has been seen in the general population, its frequency is not hig h enough to rule out a pathogenic role. Glutamic acid (Glu) at position 508 is n ot conserved in mammals or evolutionarily distant species and 8 species (tenrec, rock pigeon, american alligator, lizard, and 4 turtle species) carry a glutamin e (Gln) at this position, raising the possibility that this change may be tolera ted. Additional computational prediction tools suggest that the p.Glu508Gln vari ant may not impact the protein, though this information is not predictive enough to rule out pathogenicity. In summary, while the clinical significance of the p .Glu508Gln variant is uncertain, its presence in other species suggests that it is more likely to be benign. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Aug 21, 2022

This sequence change replaces glutamic acid, which is acidic and polar, with glutamine, which is neutral and polar, at codon 508 of the KARS protein (p.Glu508Gln). This variant is present in population databases (rs376538590, gnomAD 0.05%). 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: 228756). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.081

BayesDel_addAF

Benign

-0.28

BayesDel_noAF

Benign

-0.30

Cadd

Benign

Dann

Benign

0.97

Eigen

Benign

-0.49

Eigen_PC

Benign

-0.34

FATHMM_MKL

Uncertain

0.76

LIST_S2

Uncertain

0.92

D;D

M_CAP

Benign

0.026

MetaRNN

Benign

0.062

T;T

MetaSVM

Benign

-0.64

MutationTaster

Benign

0.96

D;N;N

PrimateAI

Benign

0.34

PROVEAN

Benign

-0.11

N;N

REVEL

Benign

0.13

Sift

Benign

0.046

D;D

Sift4G

Uncertain

0.035

D;D

Polyphen

0.0010

B;B

Vest4

0.15

MVP

0.86

MPC

0.092

ClinPred

0.059

GERP RS

1.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.43

gMVP

0.78

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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