chr16-75631248-G-A

Position:

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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R420H) has been classified as Uncertain significance.

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:6

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/exons	MANE
KARS1	NM_005548.3 linkuse as main transcript	c.1258C>T	p.Arg420Cys	missense_variant	10/14	ENST00000302445.8
KARS1	NM_001130089.2 linkuse as main transcript	c.1342C>T	p.Arg448Cys	missense_variant	11/15
KARS1	NM_001378148.1 linkuse as main transcript	c.790C>T	p.Arg264Cys	missense_variant	10/14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KARS1	ENST00000302445.8 linkuse as main transcript	c.1258C>T	p.Arg420Cys	missense_variant	10/14	1	NM_005548.3	A1	Q15046-1
KARS1	ENST00000319410.9 linkuse as main transcript	c.1342C>T	p.Arg448Cys	missense_variant	11/15	1		P4	Q15046-2
KARS1	ENST00000568378.5 linkuse as main transcript	c.147-3259C>T		intron_variant		5
KARS1	ENST00000564578.5 linkuse as main transcript	c.*801C>T		3_prime_UTR_variant, NMD_transcript_variant	10/14	5

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:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2023	KARS1: BS2 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 09, 2020	This variant is associated with the following publications: (PMID: 26762739) -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 14, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 22, 2024	- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Nov 24, 2014

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). -

KARS1-related disorder

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 11, 2022

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

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

MutationTaster

Benign

1.0

D;D;D

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