rs11557669

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_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. 15/22 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

Publications

2 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: G2P, Labcorp Genetics (formerly Invitae)
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: Likely_benign. The variant received -4 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.05498287).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005548.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
KARS1	NM_005548.3	MANE Select	c.274G>C	p.Glu92Gln	missense	Exon 3 of 14	NP_005539.1	Q15046-1
KARS1	NM_001130089.2		c.358G>C	p.Glu120Gln	missense	Exon 4 of 15	NP_001123561.1	Q15046-2
KARS1	NM_001378148.1		c.-195G>C		5_prime_UTR	Exon 3 of 14	NP_001365077.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
KARS1	ENST00000302445.8	TSL:1 MANE Select	c.274G>C	p.Glu92Gln	missense	Exon 3 of 14	ENSP00000303043.3	Q15046-1
KARS1	ENST00000319410.9	TSL:1	c.358G>C	p.Glu120Gln	missense	Exon 4 of 15	ENSP00000325448.5	Q15046-2
KARS1	ENST00000566560.5	TSL:1	n.388G>C		non_coding_transcript_exon	Exon 3 of 7

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

GnomAD2 exomes

AF:

0.000453

AC:

114

AN:

251486

AF XY:

0.000471

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 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

African (AFR)

AF:

0.000179

AC:

AN:

33478

American (AMR)

AF:

0.000246

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86250

European-Finnish (FIN)

AF:

0.0000374

AC:

AN:

53418

Middle Eastern (MID)

AF:

0.000526

AC:

AN:

5704

European-Non Finnish (NFE)

AF:

0.000573

AC:

637

AN:

1111870

Other (OTH)

AF:

0.000596

AC:

AN:

60384

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

117

156

195

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

120

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000428

AC:

AN:

151970

Hom.:

Cov.:

AF XY:

0.000350

AC XY:

AN XY:

74244

show subpopulations

African (AFR)

AF:

0.0000724

AC:

AN:

41428

American (AMR)

AF:

0.000590

AC:

AN:

15256

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3464

East Asian (EAS)

AF:

0.00

AC:

AN:

5150

South Asian (SAS)

AF:

0.00

AC:

AN:

4812

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10534

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000750

AC:

AN:

68014

Other (OTH)

AF:

0.000950

AC:

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

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

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

not specified (3)

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 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.27

BayesDel_noAF

Benign

-0.25

CADD

Benign

(source)

DANN

Benign

0.83

DEOGEN2

Benign

0.17

Eigen

Benign

-0.0099

Eigen_PC

Benign

0.12

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Pathogenic

0.98

M_CAP

Benign

0.025

MetaRNN

Benign

0.055

MetaSVM

Benign

-0.82

MutationAssessor

Uncertain

2.1

PhyloP100

5.8

PrimateAI

Benign

0.46

PROVEAN

Benign

-1.4

REVEL

Benign

0.17

Sift

Benign

0.41

Sift4G

Benign

0.53

Polyphen

0.032

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

Mutation Taster

=38/62

disease causing

(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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over