16-75627905-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_005548.3(KARS1):c.1784C>G(p.Thr595Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0539 in 1,578,048 control chromosomes in the GnomAD database, including 5,488 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.12 (2288 hom., cov: 33)
  • Exomes 𝑓: 0.047 (3200 hom.)
• Consequence: KARS1 NM_005548.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 6.42

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.003862083).
• BP6: Variant 16-75627905-G-C is Benign according to our data. Variant chr16-75627905-G-C is described in ClinVar as [Benign]. Clinvar id is 226682.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-75627905-G-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.317 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KARS1	NM_005548.3	c.1784C>G	p.Thr595Ser	missense_variant	14/14	ENST00000302445.8
KARS1	NM_001130089.2	c.1868C>G	p.Thr623Ser	missense_variant	15/15
KARS1	NM_001378148.1	c.1316C>G	p.Thr439Ser	missense_variant	14/14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KARS1	ENST00000302445.8	c.1784C>G	p.Thr595Ser	missense_variant	14/14	1	NM_005548.3	A1

Frequencies

GnomAD3 genomes AF: 0.119 AC: 18163 AN: 152128 Hom.: 2283 Cov.: 33

Gnomad AFR AF: 0.322

Gnomad AMI AF: 0.0219

Gnomad AMR AF: 0.0499

Gnomad ASJ AF: 0.0421

Gnomad EAS AF: 0.00519

Gnomad SAS AF: 0.0547

Gnomad FIN AF: 0.0644

Gnomad MID AF: 0.0348

Gnomad NFE AF: 0.0405

Gnomad OTH AF: 0.0828

GnomAD3 exomes AF: 0.0584 AC: 14678 AN: 251416 Hom.: 1176 AF XY: 0.0539 AC XY: 7318 AN XY: 135896

Gnomad AFR exome AF: 0.328

Gnomad AMR exome AF: 0.0265

Gnomad ASJ exome AF: 0.0392

Gnomad EAS exome AF: 0.00511

Gnomad SAS exome AF: 0.0532

Gnomad FIN exome AF: 0.0652

Gnomad NFE exome AF: 0.0405

Gnomad OTH exome AF: 0.0482

GnomAD4 exome AF: 0.0468 AC: 66796 AN: 1425802 Hom.: 3200 Cov.: 26 AF XY: 0.0460 AC XY: 32736 AN XY: 711752

Gnomad4 AFR exome AF: 0.330

Gnomad4 AMR exome AF: 0.0290

Gnomad4 ASJ exome AF: 0.0414

Gnomad4 EAS exome AF: 0.00539

Gnomad4 SAS exome AF: 0.0520

Gnomad4 FIN exome AF: 0.0677

Gnomad4 NFE exome AF: 0.0386

Gnomad4 OTH exome AF: 0.0603

GnomAD4 genome AF: 0.120 AC: 18201 AN: 152246 Hom.: 2288 Cov.: 33 AF XY: 0.116 AC XY: 8656 AN XY: 74444

Gnomad4 AFR AF: 0.322

Gnomad4 AMR AF: 0.0498

Gnomad4 ASJ AF: 0.0421

Gnomad4 EAS AF: 0.00501

Gnomad4 SAS AF: 0.0545

Gnomad4 FIN AF: 0.0644

Gnomad4 NFE AF: 0.0405

Gnomad4 OTH AF: 0.0819

Alfa AF: 0.0430 Hom.: 109

Bravo AF: 0.127

TwinsUK AF: 0.0334 AC: 124

ALSPAC AF: 0.0415 AC: 160

ESP6500AA AF: 0.324 AC: 1426

ESP6500EA AF: 0.0405 AC: 348

ExAC AF: 0.0657 AC: 7980

Asia WGS AF: 0.0550 AC: 191 AN: 3478

EpiCase AF: 0.0399

EpiControl AF: 0.0351

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 24, 2014	Thr623Ser in exon 15 of KARS: This variant is not expected to have clinical sign ificance because it has been identified in 32.4% (1426/4396) of African American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http ://evs.gs.washington.edu/EVS; dbSNP rs6834). -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 09, 2017	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. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

Autosomal recessive nonsyndromic hearing loss 89 Benign:1

Benign, criteria provided, single submitter

clinical testing

Mendelics

May 28, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.38
Cadd	Benign	22
Dann	Uncertain	0.98
Eigen	Benign	-0.20
Eigen_PC	Benign	0.057
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.51	T;T
MetaRNN	Benign	0.0039	T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	P;P;P
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-0.11	N;N
REVEL	Uncertain	0.31
Sift	Benign	0.18	T;T
Sift4G	Benign	0.079	T;T
Polyphen		0.021	B;B
Vest4		0.090
MutPred		0.046		.;Loss of glycosylation at T595 (P = 0.049);
MPC		0.084
ClinPred		0.016	T
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.056
gMVP		0.66

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: rs6834; hg19: chr16-75661803; COSMIC: COSV56692024; COSMIC: COSV56692024;