chr16-75636503-A-G
Variant summary
Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2PP3_ModeratePP5
The NM_005548.3(KARS1):c.433T>C(p.Tyr145His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000089 in 1,461,472 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y145C) has been classified as Uncertain significance.
Frequency
Consequence
NM_005548.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 5 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
KARS1 | NM_005548.3 | c.433T>C | p.Tyr145His | missense_variant | 4/14 | ENST00000302445.8 | |
KARS1 | NM_001130089.2 | c.517T>C | p.Tyr173His | missense_variant | 5/15 | ||
KARS1 | NM_001378148.1 | c.-36T>C | 5_prime_UTR_variant | 4/14 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
KARS1 | ENST00000302445.8 | c.433T>C | p.Tyr145His | missense_variant | 4/14 | 1 | NM_005548.3 | A1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 exomes AF: 0.0000278 AC: 7AN: 251436Hom.: 0 AF XY: 0.0000515 AC XY: 7AN XY: 135900
GnomAD4 exome AF: 0.00000890 AC: 13AN: 1461472Hom.: 0 Cov.: 30 AF XY: 0.0000151 AC XY: 11AN XY: 727078
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Autosomal recessive nonsyndromic hearing loss 89 Pathogenic:2
Pathogenic, no assertion criteria provided | research | Department of Molecular and Human Genetics, Baylor College of Medicine | Jan 17, 2014 | - - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Jul 11, 2013 | - - |
Nonsyndromic genetic hearing loss Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Center of Genomic medicine, Geneva, University Hospital of Geneva | Nov 20, 2017 | This homozygous variant was identified in a female patient with non-syndromic and progressive deafness, due to bilateral vestibulo-cochlear dysfunction. One of her two brothers who is also deaf also harbours this variant in a homozygous state. - |
Leukoencephalopathy, progressive, infantile-onset, with or without deafness Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | 3billion | Jan 03, 2022 | Same nucleotide change resulting in same amino acid change has been previously reported to be associated with KARS1 related disorder (ClinVar ID: VCV000060752, PS1_P). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000028, PM2_M). A missense variant is a common mechanism associated with Leukoencephalopathy (PP2_P).Therefore, this variant is classified as uncertain significance according to the recommendation of ACMG/AMP guideline. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at