16-75640298-C-T

Position:

• chr16-75640298-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_005548.3(KARS1):​c.274G>A​(p.Glu92Lys) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 31)
• Consequence: KARS1 NM_005548.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.82

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.24495873).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KARS1	NM_005548.3	c.274G>A	p.Glu92Lys	missense_variant	3/14	ENST00000302445.8	NP_005539.1
KARS1	NM_001130089.2	c.358G>A	p.Glu120Lys	missense_variant	4/15		NP_001123561.1
KARS1	NM_001378148.1	c.-195G>A		5_prime_UTR_variant	3/14		NP_001365077.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KARS1	ENST00000302445.8	c.274G>A	p.Glu92Lys	missense_variant	3/14	1	NM_005548.3	ENSP00000303043.3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Uncertain	0.084	D
BayesDel_noAF	Benign	-0.12
CADD	Uncertain	24
DANN	Benign	0.85
DEOGEN2	Benign	0.17	.;T;.
Eigen	Benign	-0.18
Eigen_PC	Benign	-0.0019
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.97	D;D;D
M_CAP	Benign	0.027	D
MetaRNN	Benign	0.24	T;T;T
MetaSVM	Benign	-0.86	T
MutationAssessor	Benign	1.2	.;L;.
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-1.3	N;N;N
REVEL	Benign	0.20
Sift	Benign	0.64	T;T;T
Sift4G	Benign	0.88	T;T;T
Polyphen		0.0	B;B;.
Vest4		0.53
MutPred		0.41		.;Gain of ubiquitination at E92 (P = 0.0192);.;
MVP		0.60
MPC		0.11
ClinPred		0.55	D
GERP RS		5.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.51
gMVP		0.59

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: rs11557669; hg19: chr16-75674196;