rs77573084

chr16-75631248-G-A

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BS1 BS2

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
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 10.0

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 -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 GnomAdExome at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KARS1	NM_005548.3	c.1258C>T	p.Arg420Cys	missense_variant	10/14	ENST00000302445.8
KARS1	NM_001130089.2	c.1342C>T	p.Arg448Cys	missense_variant	11/15
KARS1	NM_001378148.1	c.790C>T	p.Arg264Cys	missense_variant	10/14

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.00193 AC: 294 AN: 152164 Hom.: 1 Cov.: 33

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.: 2 AF XY: 0.00154 AC XY: 209 AN XY: 135536

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.: 11 Cov.: 32 AF XY: 0.00290 AC XY: 2111 AN XY: 727044

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.: 1 Cov.: 33 AF XY: 0.00161 AC XY: 120 AN XY: 74456

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.: 4

Bravo AF: 0.00208

TwinsUK AF: 0.00378 AC: 14

ALSPAC AF: 0.00337 AC: 13

ESP6500AA AF: 0.000910 AC: 4

ESP6500EA AF: 0.00302 AC: 26

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

Submissions by phenotype

not provided Benign:4

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

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	T
BayesDel_noAF	Pathogenic	0.31
Cadd	Pathogenic	31
Dann	Uncertain	1.0
Eigen	Pathogenic	0.69
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.90	D;D
M_CAP	Uncertain	0.13	D
MetaRNN	Benign	0.10	T;T
MetaSVM	Uncertain	0.15	D
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.64	T
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	T
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

Other links and lift over

dbSNP: rs77573084; hg19: chr16-75665146; COSMIC: COSV56692206; COSMIC: COSV56692206;