rs5030748

Variant names:

• chr16-75641711-T-C
• rs5030748
• NM_005548.3:c.75A>G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_005548.3(KARS1):​c.75A>G​(p.Arg25Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0929 in 1,613,536 control chromosomes in the GnomAD database, including 7,895 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.069 (488 hom., cov: 31)
  • Exomes 𝑓: 0.095 (7407 hom.)
• Consequence: KARS1 NM_005548.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.265

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=-0.6).
• BP6: Variant 16-75641711-T-C is Benign according to our data. Variant chr16-75641711-T-C is described in ClinVar as [Benign]. Clinvar id is 226680.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-75641711-T-C is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.265 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.103 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KARS1	NM_005548.3	c.75A>G	p.Arg25Arg	synonymous_variant	Exon 2 of 14	ENST00000302445.8	NP_005539.1
KARS1	NM_001130089.2	c.159A>G	p.Arg53Arg	synonymous_variant	Exon 3 of 15		NP_001123561.1
KARS1	NM_001378148.1	c.-394A>G		5_prime_UTR_variant	Exon 2 of 14		NP_001365077.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KARS1	ENST00000302445.8	c.75A>G	p.Arg25Arg	synonymous_variant	Exon 2 of 14	1	NM_005548.3	ENSP00000303043.3

Frequencies

GnomAD3 genomes AF: 0.0689 AC: 10483 AN: 152176 Hom.: 489 Cov.: 31

Gnomad AFR AF: 0.0198

Gnomad AMI AF: 0.0647

Gnomad AMR AF: 0.0632

Gnomad ASJ AF: 0.0841

Gnomad EAS AF: 0.000577

Gnomad SAS AF: 0.0313

Gnomad FIN AF: 0.0810

Gnomad MID AF: 0.0601

Gnomad NFE AF: 0.105

Gnomad OTH AF: 0.0661

GnomAD3 exomes AF: 0.0717 AC: 18017 AN: 251200 Hom.: 853 AF XY: 0.0734 AC XY: 9973 AN XY: 135792

Gnomad AFR exome AF: 0.0189

Gnomad AMR exome AF: 0.0405

Gnomad ASJ exome AF: 0.0797

Gnomad EAS exome AF: 0.000272

Gnomad SAS exome AF: 0.0317

Gnomad FIN exome AF: 0.0772

Gnomad NFE exome AF: 0.109

Gnomad OTH exome AF: 0.0772

GnomAD4 exome AF: 0.0954 AC: 139344 AN: 1461242 Hom.: 7407 Cov.: 33 AF XY: 0.0941 AC XY: 68373 AN XY: 726952

Gnomad4 AFR exome AF: 0.0170

Gnomad4 AMR exome AF: 0.0430

Gnomad4 ASJ exome AF: 0.0813

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.0318

Gnomad4 FIN exome AF: 0.0780

Gnomad4 NFE exome AF: 0.110

Gnomad4 OTH exome AF: 0.0830

GnomAD4 genome AF: 0.0688 AC: 10477 AN: 152294 Hom.: 488 Cov.: 31 AF XY: 0.0667 AC XY: 4964 AN XY: 74472

Gnomad4 AFR AF: 0.0198

Gnomad4 AMR AF: 0.0631

Gnomad4 ASJ AF: 0.0841

Gnomad4 EAS AF: 0.000578

Gnomad4 SAS AF: 0.0313

Gnomad4 FIN AF: 0.0810

Gnomad4 NFE AF: 0.105

Gnomad4 OTH AF: 0.0640

Alfa AF: 0.0920 Hom.: 550

Bravo AF: 0.0674

Asia WGS AF: 0.0170 AC: 60 AN: 3478

EpiCase AF: 0.105

EpiControl AF: 0.108

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

May 09, 2017

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Nov 24, 2014

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Arg53Arg in exon 3 of KARS: This variant is not expected to have clinical signif icance because it does not alter an amino acid residue and is not located within the splice consensus sequence. It has been identified in 11.0% (942/8600) of Eu ropean American chromosomes from a broad population by the NHLBI Exome Sequencin g Project (http://evs.gs.washington.edu/EVS; dbSNP rs5030748). -

not provided Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.60
CADD	Benign	9.9
DANN	Benign	0.75

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: rs5030748; hg19: chr16-75675609;