chr16-75635758-A-C

Position:

chr16-75635758-A-C

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2BP4_StrongBP6

The NM_005548.3(KARS1):c.717T>G(p.Phe239Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000862 in 1,614,210 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00070 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00088 ( 1 hom. )

Consequence

KARS1
NM_005548.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6B:2

Conservation

PhyloP100: 0.432

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:

KARS1 (HGNC:):

KARS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.025331646).

BP6

Variant 16-75635758-A-C is Benign according to our data. Variant chr16-75635758-A-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 420262.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=4}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KARS1	NM_005548.3 linkuse as main transcript	c.717T>G	p.Phe239Leu	missense_variant	6/14	ENST00000302445.8	NP_005539.1	Q15046-1
KARS1	NM_001130089.2 linkuse as main transcript	c.801T>G	p.Phe267Leu	missense_variant	7/15		NP_001123561.1	Q15046-2
KARS1	NM_001378148.1 linkuse as main transcript	c.249T>G	p.Phe83Leu	missense_variant	6/14		NP_001365077.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KARS1	ENST00000302445.8 linkuse as main transcript	c.717T>G	p.Phe239Leu	missense_variant	6/14	1	NM_005548.3	ENSP00000303043.3		Q15046-1

Frequencies

GnomAD3 genomes

AF:

0.000703

AC:

107

AN:

152232

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000265

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00103

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00123

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000788

AC:

198

AN:

251404

Hom.:

AF XY:

0.000765

AC XY:

104

AN XY:

135876

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00120

Gnomad NFE exome

AF:

0.00150

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000878

AC:

1284

AN:

1461860

Hom.:

Cov.:

AF XY:

0.000831

AC XY:

604

AN XY:

727234

show subpopulations

Gnomad4 AFR exome

AF:

0.000239

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00101

Gnomad4 NFE exome

AF:

0.00106

Gnomad4 OTH exome

AF:

0.000629

GnomAD4 genome

AF:

0.000702

AC:

107

AN:

152350

Hom.:

Cov.:

AF XY:

0.000698

AC XY:

AN XY:

74508

show subpopulations

Gnomad4 AFR

AF:

0.000264

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00103

Gnomad4 NFE

AF:

0.00123

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.00105

Hom.:

Bravo

AF:

0.000484

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.00104

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000930

AC:

ExAC

AF:

0.000906

AC:

110

EpiCase

AF:

0.000654

EpiControl

AF:

0.000652

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:6Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:5Benign:1

Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Apr 04, 2020	The KARS c.801T>G; p.Phe267Leu variant (rs117188693) is reported in the literature in a homozygous individual affected with distal hereditary motor neuropathy (Zhao 2014). This variant is found in the non-Finnish European population with an overall allele frequency of 0.14% (185/129110 alleles) in the Genome Aggregation Database. The phenylalanine at codon 267 is moderately conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is tolerated. However, splicing analyses (Alamut v.2.11) predict that this variant may impact splicing by creating a novel cryptic donor site, although splicing analyses would be required to confirm this. Given the lack of additional clinical and functional data, the significance of the p.Phe267Leu variant is uncertain at this time. References: Zhao H et al. Exome sequencing reveals HINT1 mutations as a cause of distal hereditary motor neuropathy. Eur J Hum Genet. 2014 Jun;22(6):847-50. -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Oct 12, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 07, 2020	In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 24105373) -
Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 22, 2022	This sequence change replaces phenylalanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 267 of the KARS protein (p.Phe267Leu). This variant is present in population databases (rs117188693, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with KARS-related conditions. ClinVar contains an entry for this variant (Variation ID: 420262). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Aug 27, 2019

Variant classified as Uncertain Significance - Favor Benign. The p.Phe267Leu variant in KARS has been identified in the heterozygous state in two individuals with hearing loss (LMM data), but has also been identified in 0.14% (185/129110) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). This variant has been reported in ClinVar (Variation ID 420262). Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. In summary, while the clinical significance of this variant is uncertain, its frequency suggests that it is more likely to be benign. ACMG/AMP Criteria applied: BS1_Supporting. -

Hearing impairment

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Department of Otolaryngology – Head & Neck Surgery, Cochlear Implant Center

Apr 12, 2021

BS1_Strong, BP4_Supporting, BP5_ Supporting -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.56

BayesDel_addAF

Benign

-0.29

BayesDel_noAF

Benign

-0.21

CADD

Benign

7.4

DANN

Benign

0.95

DEOGEN2

Benign

0.40

.;T;.;T

Eigen

Benign

-0.95

Eigen_PC

Benign

-0.74

FATHMM_MKL

Uncertain

0.93

LIST_S2

Pathogenic

0.98

D;D;D;D

M_CAP

Benign

0.033

MetaRNN

Benign

0.025

T;T;T;T

MetaSVM

Benign

-0.99

MutationAssessor

Benign

0.34

.;N;.;.

PrimateAI

Uncertain

0.77

PROVEAN

Benign

-0.42

N;N;N;.

REVEL

Benign

0.27

Sift

Benign

0.20

T;T;T;.

Sift4G

Benign

0.20

T;T;D;.

Polyphen

0.0040

B;B;.;.

Vest4

0.47

MutPred

0.46

.;Loss of MoRF binding (P = 0.1135);.;.;

MVP

0.69

MPC

0.12

ClinPred

0.018

GERP RS

0.14

Varity_R

0.30

gMVP

0.72

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

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