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
Consequence
NM_005548.3 missense
Scores
Clinical Significance
Conservation
Publications
- autosomal recessive nonsyndromic hearing loss 89Inheritance: AR Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), G2P
- leukoencephalopathy, progressive, infantile-onset, with or without deafnessInheritance: AR Classification: STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
- Charcot-Marie-Tooth disease recessive intermediate BInheritance: AR, Unknown Classification: SUPPORTIVE, LIMITED Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)
- hearing loss, autosomal recessiveInheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
- nonsyndromic genetic hearing lossInheritance: AR Classification: LIMITED Submitted by: ClinGen
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ACMG classification
Our verdict: Uncertain_significance. The variant received 2 ACMG points.
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
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome Cov.: 34
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
not provided Uncertain:1
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:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at