Menu
GeneBe

16-75627947-T-G

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2BP4_StrongBP6_Moderate

The NM_005548.3(KARS1):c.1742A>C(p.Asn581Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000323 in 1,612,222 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/15 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000033 ( 0 hom. )

Consequence

KARS1
NM_005548.3 missense

Scores

1
12

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 0.0270
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.033758134).
BP6
Variant 16-75627947-T-G is Benign according to our data. Variant chr16-75627947-T-G is described in ClinVar as [Likely_benign]. Clinvar id is 1120140.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
KARS1NM_005548.3 linkuse as main transcriptc.1742A>C p.Asn581Thr missense_variant 14/14 ENST00000302445.8
KARS1NM_001130089.2 linkuse as main transcriptc.1826A>C p.Asn609Thr missense_variant 15/15
KARS1NM_001378148.1 linkuse as main transcriptc.1274A>C p.Asn425Thr missense_variant 14/14

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
KARS1ENST00000302445.8 linkuse as main transcriptc.1742A>C p.Asn581Thr missense_variant 14/141 NM_005548.3 A1Q15046-1

Frequencies

GnomAD3 genomes
AF:
0.0000263
AC:
4
AN:
152242
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00
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:
0.0000588
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000239
AC:
6
AN:
251292
Hom.:
0
AF XY:
0.0000294
AC XY:
4
AN XY:
135864
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000528
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000329
AC:
48
AN:
1459862
Hom.:
0
Cov.:
28
AF XY:
0.0000330
AC XY:
24
AN XY:
726460
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
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:
0.0000414
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000263
AC:
4
AN:
152360
Hom.:
0
Cov.:
33
AF XY:
0.0000134
AC XY:
1
AN XY:
74522
show subpopulations
Gnomad4 AFR
AF:
0.00
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:
0.0000588
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000658
Hom.:
0
Bravo
AF:
0.0000302
ExAC
AF:
0.0000247
AC:
3
EpiCase
AF:
0.00
EpiControl
AF:
0.0000593

ClinVar

Significance: Likely benign
Submissions summary: Benign:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Benign:1
Likely benign, criteria provided, single submitterclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineJun 02, 2020The p.Asn609Thr variant in KARS is classified as likely benign due to a lack of conservation across species. >10 mammals carry a threonine (Thr) at this position despite high nearby amino acid conservation. ACMG/AMP Criteria applied: BP4_Strong. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.056
BayesDel_addAF
Benign
-0.41
T
BayesDel_noAF
Benign
-0.56
Cadd
Benign
5.4
Dann
Benign
0.72
Eigen
Benign
-1.2
Eigen_PC
Benign
-1.2
FATHMM_MKL
Benign
0.24
N
LIST_S2
Benign
0.40
T
M_CAP
Benign
0.0069
T
MetaRNN
Benign
0.034
T
MutationTaster
Benign
1.0
N;N;N
PROVEAN
Benign
-0.91
N
Sift
Pathogenic
0.0
D
Vest4
0.079
MVP
0.12
ClinPred
0.012
T
GERP RS
-1.3
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
2.8

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.

Other links and lift over

dbSNP: rs117561624; hg19: chr16-75661845; API