chr16-75631248-G-A

Variant names:

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

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]

KARS1 links:

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
KARS1	NM_005548.3 link	c.1258C>T	p.Arg420Cys	missense_variant	Exon 10 of 14	ENST00000302445.8	NP_005539.1	Q15046-1
KARS1	NM_001130089.2 link	c.1342C>T	p.Arg448Cys	missense_variant	Exon 11 of 15		NP_001123561.1	Q15046-2
KARS1	NM_001378148.1 link	c.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
KARS1	ENST00000302445.8 link	c.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.:

Cov.:

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.:

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.:

Cov.:

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.:

Cov.:

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.:

Bravo

AF:

0.00208

TwinsUK

AF:

0.00378

AC:

ALSPAC

AF:

0.00337

AC:

ESP6500AA

AF:

0.000910

AC:

ESP6500EA

AF:

0.00302

AC:

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

Feb 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

KARS1: BS1, BS2 -

Dec 09, 2020

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 26762739) -

Oct 14, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 09, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified

Benign:2

Nov 24, 2014

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Arg448Cys 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). -

Dec 10, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant 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

Feb 11, 2022

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This 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

BayesDel_noAF

Pathogenic

0.31

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.83

.;D

Eigen

Pathogenic

0.69

Eigen_PC

Pathogenic

0.76

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.90

D;D

M_CAP

Uncertain

0.13

MetaRNN

Benign

0.10

T;T

MetaSVM

Uncertain

0.15

MutationAssessor

Uncertain

2.8

.;M

PrimateAI

Uncertain

0.64

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

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.

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