rs16941301

Positions:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The ENST00000302445.8(KARS1):c.1079-7C>T variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0218 in 1,614,092 control chromosomes in the GnomAD database, including 672 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.032 ( 119 hom., cov: 32)

Exomes 𝑓: 0.021 ( 553 hom. )

Consequence

KARS1
ENST00000302445.8 splice_region, splice_polypyrimidine_tract, intron

Scores

Splicing: ADA: 0.0002188

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 0.551

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:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.52).

BP6

Variant 16-75631596-G-A is Benign according to our data. Variant chr16-75631596-G-A is described in ClinVar as [Benign]. Clinvar id is 226678.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-75631596-G-A is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0649 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	MANE	Protein
KARS1	NM_005548.3 linkuse as main transcript	c.1079-7C>T	splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant	ENST00000302445.8	NP_005539.1
KARS1	NM_001130089.2 linkuse as main transcript	c.1163-7C>T	splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		NP_001123561.1
KARS1	NM_001378148.1 linkuse as main transcript	c.611-7C>T	splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		NP_001365077.1

Ensembl

Gene	Transcript	HGVSc	Effect	TSL	MANE	Protein	Appris	UniProt
KARS1	ENST00000302445.8 linkuse as main transcript	c.1079-7C>T	splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant	1	NM_005548.3	ENSP00000303043	A1	Q15046-1
KARS1	ENST00000319410.9 linkuse as main transcript	c.1163-7C>T	splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant	1		ENSP00000325448	P4	Q15046-2
KARS1	ENST00000568378.5 linkuse as main transcript	c.147-3607C>T	intron_variant	5		ENSP00000454512
KARS1	ENST00000564578.5 linkuse as main transcript	c.*622-7C>T	splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant, NMD_transcript_variant	5		ENSP00000455818

Frequencies

GnomAD3 genomes

AF:

0.0322

AC:

4896

AN:

152168

Hom.:

118

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0670

Gnomad AMI

AF:

0.0373

Gnomad AMR

AF:

0.0188

Gnomad ASJ

AF:

0.0314

Gnomad EAS

AF:

0.0302

Gnomad SAS

AF:

0.0578

Gnomad FIN

AF:

0.00593

Gnomad MID

AF:

0.0601

Gnomad NFE

AF:

0.0163

Gnomad OTH

AF:

0.0320

GnomAD3 exomes

AF:

0.0268

AC:

6734

AN:

251356

Hom.:

165

AF XY:

0.0281

AC XY:

3820

AN XY:

135854

show subpopulations

Gnomad AFR exome

AF:

0.0690

Gnomad AMR exome

AF:

0.0144

Gnomad ASJ exome

AF:

0.0304

Gnomad EAS exome

AF:

0.0261

Gnomad SAS exome

AF:

0.0684

Gnomad FIN exome

AF:

0.00462

Gnomad NFE exome

AF:

0.0175

Gnomad OTH exome

AF:

0.0231

GnomAD4 exome

AF:

0.0207

AC:

30231

AN:

1461806

Hom.:

553

Cov.:

AF XY:

0.0221

AC XY:

16054

AN XY:

727210

show subpopulations

Gnomad4 AFR exome

AF:

0.0723

Gnomad4 AMR exome

AF:

0.0157

Gnomad4 ASJ exome

AF:

0.0316

Gnomad4 EAS exome

AF:

0.0259

Gnomad4 SAS exome

AF:

0.0661

Gnomad4 FIN exome

AF:

0.00594

Gnomad4 NFE exome

AF:

0.0156

Gnomad4 OTH exome

AF:

0.0256

GnomAD4 genome

AF:

0.0322

AC:

4900

AN:

152286

Hom.:

119

Cov.:

AF XY:

0.0319

AC XY:

2377

AN XY:

74472

show subpopulations

Gnomad4 AFR

AF:

0.0670

Gnomad4 AMR

AF:

0.0188

Gnomad4 ASJ

AF:

0.0314

Gnomad4 EAS

AF:

0.0303

Gnomad4 SAS

AF:

0.0572

Gnomad4 FIN

AF:

0.00593

Gnomad4 NFE

AF:

0.0163

Gnomad4 OTH

AF:

0.0317

Alfa

AF:

0.0194

Hom.:

Bravo

AF:

0.0342

Asia WGS

AF:

0.0660

AC:

228

AN:

3478

EpiCase

AF:

0.0172

EpiControl

AF:

0.0177

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 18, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	May 23, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 24, 2014	1163-7C>T in intron 9 of KARS: This variant is not expected to have clinical sig nificance because it has been identified in 6.0% (263/4396) of African American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http: //evs.gs.washington.edu/EVS; dbSNP rs16941301). -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 03, 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.52

CADD

Benign

8.3

DANN

Benign

0.61

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00022

dbscSNV1_RF

Benign

0.0060

SpliceAI score (max)

0.020

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