16-75640298-C-G

Position:

chr16-75640298-C-G

Variant summary

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

The NM_005548.3(KARS1):c.274G>C(p.Glu92Gln) variant causes a missense change. The variant allele was found at a frequency of 0.000471 in 1,613,634 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00043 ( 0 hom., cov: 31)

Exomes 𝑓: 0.00048 ( 1 hom. )

Consequence

KARS1
NM_005548.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:7

Conservation

PhyloP100: 5.82

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 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=0.05498287).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KARS1	NM_005548.3 linkuse as main transcript	c.274G>C	p.Glu92Gln	missense_variant	3/14	ENST00000302445.8	NP_005539.1	Q15046-1
KARS1	NM_001130089.2 linkuse as main transcript	c.358G>C	p.Glu120Gln	missense_variant	4/15		NP_001123561.1	Q15046-2
KARS1	NM_001378148.1 linkuse as main transcript	c.-195G>C		5_prime_UTR_variant	3/14		NP_001365077.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KARS1	ENST00000302445.8 linkuse as main transcript	c.274G>C	p.Glu92Gln	missense_variant	3/14	1	NM_005548.3	ENSP00000303043.3		Q15046-1

Frequencies

GnomAD3 genomes

AF:

0.000428

AC:

AN:

151854

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000726

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000591

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:

0.000750

Gnomad OTH

AF:

0.000960

GnomAD3 exomes

AF:

0.000453

AC:

114

AN:

251486

Hom.:

AF XY:

0.000471

AC XY:

AN XY:

135916

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.000376

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.000826

Gnomad OTH exome

AF:

0.000651

GnomAD4 exome

AF:

0.000475

AC:

695

AN:

1461664

Hom.:

Cov.:

AF XY:

0.000426

AC XY:

310

AN XY:

727126

show subpopulations

Gnomad4 AFR exome

AF:

0.000179

Gnomad4 AMR exome

AF:

0.000246

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000374

Gnomad4 NFE exome

AF:

0.000573

Gnomad4 OTH exome

AF:

0.000596

GnomAD4 genome

AF:

0.000428

AC:

AN:

151970

Hom.:

Cov.:

AF XY:

0.000350

AC XY:

AN XY:

74244

show subpopulations

Gnomad4 AFR

AF:

0.0000724

Gnomad4 AMR

AF:

0.000590

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000750

Gnomad4 OTH

AF:

0.000950

Alfa

AF:

0.000528

Hom.:

Bravo

AF:

0.000450

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000465

AC:

ExAC

AF:

0.000535

AC:

EpiCase

AF:

0.000927

EpiControl

AF:

0.000889

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 04, 2018	Variant classified as Uncertain Significance - Favor Benign. The p.Glu120Gln var iant in KARS has been previously reported by our laboratory in 1 individual with hearing loss. This variant has also been identified in 0.08% (95/126658) of Eur opean chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broa dinstitute.org; dbSNP rs11557669). Although this variant has been seen in the ge neral population, its frequency is not high enough to rule out a pathogenic role . Computational prediction tools and conservation analysis do not provide strong support for or against an impact to the protein. In summary, while the clinical significance of the p.Glu120Gln variant is uncertain, its frequency suggests th at it is more likely to be benign. ACMG/AMP Criteria applied: None -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Mar 18, 2019	The p.Glu120Gln variant (rs11557669) has not been reported in the medical literature, or gene specific variation databases. This variant is listed in the Genome Aggregation Database (gnomAD) with an overall population frequency of 0.04 percent (identified on 122 out of 282,770 chromosomes), and has been reported to ClinVar database (Variation ID: 228758). The glutamic acid at position 120 is moderately conserved and computational analyses of the effects of the p.Glu120Gln variant on protein structure and function is neutral (SIFT: tolerated, PolyPhen-2: benign). Given the borderline rarity in the population, the pathogenicity of this variant can not be completely ruled out. Overall, there is not enough evidence to classify the p.Glu120Gln variant with certainty. -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Sep 01, 2021	The c.358G>C (p.E120Q) alteration is located in exon 4 (coding exon 3) of the KARS gene. This alteration results from a G to C substitution at nucleotide position 358, causing the glutamic acid (E) at amino acid position 120 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Sep 28, 2022	This sequence change replaces glutamic acid, which is acidic and polar, with glutamine, which is neutral and polar, at codon 120 of the KARS protein (p.Glu120Gln). This variant is present in population databases (rs11557669, gnomAD 0.08%). 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: 228758). 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Dec 08, 2022	Reported in a patient with language impairment in published literature (Chen et al., 2017); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 28440294) -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Nov 28, 2022	BP4 -

Charcot-Marie-Tooth disease recessive intermediate B;C3151351:Autosomal recessive nonsyndromic hearing loss 89;C5542996:Leukoencephalopathy, progressive, infantile-onset, with or without deafness;C5543087:Deafness, congenital, and adult-onset progressive leukoencephalopathy

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Jan 12, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.27

BayesDel_noAF

Benign

-0.25

CADD

Benign

DANN

Benign

0.83

DEOGEN2

Benign

0.17

.;T;.

Eigen

Benign

-0.0099

Eigen_PC

Benign

0.12

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Pathogenic

0.98

D;D;D

M_CAP

Benign

0.025

MetaRNN

Benign

0.055

T;T;T

MetaSVM

Benign

-0.82

MutationAssessor

Uncertain

2.1

.;M;.

PrimateAI

Benign

0.46

PROVEAN

Benign

-1.4

N;N;N

REVEL

Benign

0.17

Sift

Benign

0.41

T;T;T

Sift4G

Benign

0.53

T;T;T

Polyphen

0.032

B;B;.

Vest4

0.48

MVP

0.66

MPC

0.093

ClinPred

0.029

GERP RS

5.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.45

gMVP

0.52

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