NM_005548.3:c.1184A>T

Variant names:

• chr16-75631484-T-A
• rs780462719
• NM_005548.3:c.1184A>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_005548.3(KARS1):​c.1184A>T​(p.Asn395Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N395S) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: KARS1 NM_005548.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.28
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• autosomal recessive nonsyndromic hearing loss 89

  Inheritance: AR Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), G2P
• leukoencephalopathy, progressive, infantile-onset, with or without deafness

  Inheritance: AR Classification: STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• Charcot-Marie-Tooth disease recessive intermediate B

  Inheritance: AR, Unknown Classification: SUPPORTIVE, LIMITED Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)
• hearing loss, autosomal recessive

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• nonsyndromic genetic hearing loss

  Inheritance: AR Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KARS1	NM_005548.3	c.1184A>T	p.Asn395Ile	missense_variant	Exon 9 of 14	ENST00000302445.8	NP_005539.1
KARS1	NM_001130089.2	c.1268A>T	p.Asn423Ile	missense_variant	Exon 10 of 15		NP_001123561.1
KARS1	NM_001378148.1	c.716A>T	p.Asn239Ile	missense_variant	Exon 9 of 14		NP_001365077.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KARS1	ENST00000302445.8	c.1184A>T	p.Asn395Ile	missense_variant	Exon 9 of 14	1	NM_005548.3	ENSP00000303043.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Oct 16, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces asparagine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 423 of the KARS protein (p.Asn423Ile). This variant is not present in population databases (gnomAD no frequency). 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: 2042517). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt KARS protein function with a negative predictive value of 80%. 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Uncertain	0.059	T
BayesDel_noAF	Benign	-0.15
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.77	.;D
Eigen	Benign	-0.34
Eigen_PC	Benign	-0.25
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Uncertain	0.97	D;D
M_CAP	Uncertain	0.11	D
MetaRNN	Uncertain	0.57	D;D
MetaSVM	Benign	-0.36	T
MutationAssessor	Uncertain	2.2	.;M
PhyloP100		2.3
PrimateAI	Benign	0.35	T
PROVEAN	Uncertain	-4.3	D;D
REVEL	Uncertain	0.43
Sift	Uncertain	0.018	D;D
Sift4G	Uncertain	0.048	D;T
Polyphen		0.0080	B;B
Vest4		0.55
MutPred		0.66		.;Loss of helix (P = 0.0626);
MVP		0.80
MPC		0.15
ClinPred		0.97	D
GERP RS		0.72
Varity_R		0.86
gMVP		0.80

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

Other links and lift over

dbSNP: rs780462719; hg19: chr16-75665382;