rs143267922

Positions:

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_005548.3(KARS1):c.1674C>T(p.Leu558=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000915 in 1,614,046 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0024 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00076 ( 5 hom. )

Consequence

KARS1
NM_005548.3 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: 0.474

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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.54).

BP6

Variant 16-75628590-G-A is Benign according to our data. Variant chr16-75628590-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 226681.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-75628590-G-A is described in Lovd as [Likely_benign].

BP7

Synonymous conserved (PhyloP=0.474 with no splicing effect.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00239 (364/152358) while in subpopulation AFR AF= 0.00637 (265/41582). AF 95% confidence interval is 0.00574. There are 0 homozygotes in gnomad4. There are 168 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
KARS1	NM_005548.3 linkuse as main transcript	c.1674C>T	p.Leu558=	synonymous_variant	13/14	ENST00000302445.8	NP_005539.1
KARS1	NM_001130089.2 linkuse as main transcript	c.1758C>T	p.Leu586=	synonymous_variant	14/15		NP_001123561.1
KARS1	NM_001378148.1 linkuse as main transcript	c.1206C>T	p.Leu402=	synonymous_variant	13/14		NP_001365077.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KARS1	ENST00000302445.8 linkuse as main transcript	c.1674C>T	p.Leu558=	synonymous_variant	13/14	1	NM_005548.3	ENSP00000303043	A1	Q15046-1

Frequencies

GnomAD3 genomes

AF:

0.00240

AC:

365

AN:

152240

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00639

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00301

Gnomad ASJ

AF:

0.00346

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0190

Gnomad NFE

AF:

0.000456

Gnomad OTH

AF:

0.00239

GnomAD3 exomes

AF:

0.00134

AC:

337

AN:

251416

Hom.:

AF XY:

0.00118

AC XY:

160

AN XY:

135896

show subpopulations

Gnomad AFR exome

AF:

0.00720

Gnomad AMR exome

AF:

0.00228

Gnomad ASJ exome

AF:

0.00427

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000748

Gnomad OTH exome

AF:

0.00212

GnomAD4 exome

AF:

0.000761

AC:

1113

AN:

1461688

Hom.:

Cov.:

AF XY:

0.000730

AC XY:

531

AN XY:

727148

show subpopulations

Gnomad4 AFR exome

AF:

0.00735

Gnomad4 AMR exome

AF:

0.00241

Gnomad4 ASJ exome

AF:

0.00383

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000448

Gnomad4 OTH exome

AF:

0.00224

GnomAD4 genome

AF:

0.00239

AC:

364

AN:

152358

Hom.:

Cov.:

AF XY:

0.00225

AC XY:

168

AN XY:

74510

show subpopulations

Gnomad4 AFR

AF:

0.00637

Gnomad4 AMR

AF:

0.00294

Gnomad4 ASJ

AF:

0.00346

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000456

Gnomad4 OTH

AF:

0.00236

Alfa

AF:

0.00183

Hom.:

Bravo

AF:

0.00326

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.000600

EpiControl

AF:

0.00119

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:7

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 26, 2024	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	KARS1: BP4, BP7 -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 14, 2019	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 30, 2023	- -

not specified

Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 04, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 24, 2014	Leu586Leu in exon 14 of KARS: This variant is not expected to have clinical sign ificance because it does not alter an amino acid residue and is not located with in the splice consensus sequence. It has been identified in 0.6% (27/4396) of Af rican American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS; dbSNP rs143267922). -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.54

CADD

Benign

8.0

DANN

Benign

0.63

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.

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