chr16-75631248-G-A

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_ModerateBP6_Very_StrongBS1BS2

The NM_005548.3(KARS1):​c.1258C>T​(p.Arg420Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00292 in 1,613,744 control chromosomes in the GnomAD database, including 12 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0019 ( 1 hom., cov: 33)
Exomes 𝑓: 0.0030 ( 11 hom. )

Consequence

KARS1
NM_005548.3 missense

Scores

7
7
5

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 10.0
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 Benign. Variant got -18 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.10187775).
BP6
Variant 16-75631248-G-A is Benign according to our data. Variant chr16-75631248-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 226679.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-75631248-G-A is described in Lovd as [Likely_benign].
BS1
Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00193 (294/152282) while in subpopulation NFE AF= 0.00378 (257/68020). AF 95% confidence interval is 0.0034. There are 1 homozygotes in gnomad4. There are 120 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
BS2
High Homozygotes in GnomAdExome4 at 11 AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
KARS1NM_005548.3 linkc.1258C>T p.Arg420Cys missense_variant Exon 10 of 14 ENST00000302445.8 NP_005539.1 Q15046-1
KARS1NM_001130089.2 linkc.1342C>T p.Arg448Cys missense_variant Exon 11 of 15 NP_001123561.1 Q15046-2
KARS1NM_001378148.1 linkc.790C>T p.Arg264Cys missense_variant Exon 10 of 14 NP_001365077.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
KARS1ENST00000302445.8 linkc.1258C>T p.Arg420Cys missense_variant Exon 10 of 14 1 NM_005548.3 ENSP00000303043.3 Q15046-1

Frequencies

GnomAD3 genomes
AF:
0.00193
AC:
294
AN:
152164
Hom.:
1
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.000700
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000458
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:
0.00378
Gnomad OTH
AF:
0.000479
GnomAD3 exomes
AF:
0.00149
AC:
374
AN:
250636
Hom.:
2
AF XY:
0.00154
AC XY:
209
AN XY:
135536
show subpopulations
Gnomad AFR exome
AF:
0.000494
Gnomad AMR exome
AF:
0.000377
Gnomad ASJ exome
AF:
0.0000996
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000327
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00306
Gnomad OTH exome
AF:
0.000653
GnomAD4 exome
AF:
0.00302
AC:
4413
AN:
1461462
Hom.:
11
Cov.:
32
AF XY:
0.00290
AC XY:
2111
AN XY:
727044
show subpopulations
Gnomad4 AFR exome
AF:
0.000777
Gnomad4 AMR exome
AF:
0.000515
Gnomad4 ASJ exome
AF:
0.0000383
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.0000562
Gnomad4 NFE exome
AF:
0.00376
Gnomad4 OTH exome
AF:
0.00306
GnomAD4 genome
AF:
0.00193
AC:
294
AN:
152282
Hom.:
1
Cov.:
33
AF XY:
0.00161
AC XY:
120
AN XY:
74456
show subpopulations
Gnomad4 AFR
AF:
0.000698
Gnomad4 AMR
AF:
0.000458
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00378
Gnomad4 OTH
AF:
0.000474
Alfa
AF:
0.00304
Hom.:
4
Bravo
AF:
0.00208
TwinsUK
AF:
0.00378
AC:
14
ALSPAC
AF:
0.00337
AC:
13
ESP6500AA
AF:
0.000910
AC:
4
ESP6500EA
AF:
0.00302
AC:
26
ExAC
AF:
0.00133
AC:
162
EpiCase
AF:
0.00300
EpiControl
AF:
0.00297

ClinVar

Significance: Benign/Likely benign
Submissions summary: Benign:7
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Benign:4
Benign, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenFeb 01, 2025KARS1: BS1, BS2 -
Likely benign, criteria provided, single submitterclinical testingGeneDxDec 09, 2020This variant is associated with the following publications: (PMID: 26762739) -
Likely benign, criteria provided, single submitterclinical testingARUP Laboratories, Molecular Genetics and Genomics, ARUP LaboratoriesOct 14, 2023- -
Likely benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpDec 09, 2024- -
not specified Benign:2
Benign, criteria provided, single submitterclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineNov 24, 2014Arg448Cys in exon 11 of KARS: This variant is not expected to have clinical sign ificance because it has been identified in 0.3% (26/8600) of European American c hromosomes from a broad population by the NHLBI Exome Sequencing Project (http:/ /evs.gs.washington.edu/EVS; dbSNP rs77573084). -
Likely benign, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpDec 10, 2024Variant summary: KARS1 c.1342C>T (p.Arg448Cys) results in a non-conservative amino acid change located in the tRNA synthetases class II (D, K and N) domain (IPR004364) of the encoded protein sequence. Three of four in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0029 in 1613744 control chromosomes in the gnomAD database, including 12 homozygotes. The observed variant frequency is approximately 2.61 fold of the estimated maximal expected allele frequency for a pathogenic variant in KARS1 causing Leukoencephalopathy, progressive, infantile-onset, with or without deafness phenotype (0.0011). c.1342C>T has been reported in the presumed heterozygous state in the literature in association with hereditary motor neuropathy (example, Antoniadi_2015) without strong evidence for causality. These report(s) do not provide unequivocal conclusions about association of the variant with KARS1-related conditions. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. ClinVar contains an entry for this variant (Variation ID: 226679). Based on the evidence outlined above, the variant was classified as likely benign. -
KARS1-related disorder Benign:1
Likely benign, no assertion criteria providedclinical testingPreventionGenetics, part of Exact SciencesFeb 11, 2022This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.12
BayesDel_addAF
Uncertain
0.060
T
BayesDel_noAF
Pathogenic
0.31
CADD
Pathogenic
31
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.83
.;D
Eigen
Pathogenic
0.69
Eigen_PC
Pathogenic
0.76
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.90
D;D
M_CAP
Uncertain
0.13
D
MetaRNN
Benign
0.10
T;T
MetaSVM
Uncertain
0.15
D
MutationAssessor
Uncertain
2.8
.;M
PrimateAI
Uncertain
0.64
T
PROVEAN
Pathogenic
-4.5
D;D
REVEL
Pathogenic
0.68
Sift
Benign
0.12
T;T
Sift4G
Benign
0.16
T;T
Polyphen
0.42
B;D
Vest4
0.87
MVP
0.91
MPC
0.55
ClinPred
0.075
T
GERP RS
5.9
Varity_R
0.78
gMVP
0.82

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.

Other links and lift over

dbSNP: rs77573084; hg19: chr16-75665146; COSMIC: COSV56692206; COSMIC: COSV56692206; API