rs143267922

chr16-75628590-G-Achr16-75628590-G-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

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
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 0.474

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]

ACMG classification

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. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome at 2 AR gene

Transcripts

RefSeq

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

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.00240 AC: 365 AN: 152240 Hom.: 0 Cov.: 33

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.: 2 AF XY: 0.00118 AC XY: 160 AN XY: 135896

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.: 5 Cov.: 32 AF XY: 0.000730 AC XY: 531 AN XY: 727148

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.: 0 Cov.: 33 AF XY: 0.00225 AC XY: 168 AN XY: 74510

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.: 0

Bravo AF: 0.00326

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000600

EpiControl AF: 0.00119

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:6

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 26, 2024	- -
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 -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 30, 2023	- -
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	-	- -

not specified Benign:3

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	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 04, 2018	- -

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

Other links and lift over

dbSNP: rs143267922; hg19: chr16-75662488;