rs727503146
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_001384474.1(LOXHD1):βc.2303delGβ(p.Gly768AlafsTer165) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000773 in 1,551,416 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (β β ). Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_001384474.1 frameshift
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
LOXHD1 | NM_001384474.1 | c.2303delG | p.Gly768AlafsTer165 | frameshift_variant | Exon 17 of 41 | ENST00000642948.1 | NP_001371403.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
LOXHD1 | ENST00000642948.1 | c.2303delG | p.Gly768AlafsTer165 | frameshift_variant | Exon 17 of 41 | NM_001384474.1 | ENSP00000496347.1 | |||
LOXHD1 | ENST00000536736.5 | c.2303delG | p.Gly768AlafsTer165 | frameshift_variant | Exon 17 of 40 | 5 | ENSP00000444586.1 | |||
LOXHD1 | ENST00000441551.6 | c.2303delG | p.Gly768AlafsTer113 | frameshift_variant | Exon 17 of 39 | 5 | ENSP00000387621.2 | |||
LOXHD1 | ENST00000335730.6 | n.1616delG | non_coding_transcript_exon_variant | Exon 10 of 27 | 2 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152234Hom.: 0 Cov.: 33
GnomAD4 exome AF: 0.00000786 AC: 11AN: 1399182Hom.: 0 Cov.: 31 AF XY: 0.00000725 AC XY: 5AN XY: 690086
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152234Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 74374
ClinVar
Submissions by phenotype
not provided Pathogenic:1
For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 163919). This variant has not been reported in the literature in individuals affected with LOXHD1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Gly768Alafs*165) in the LOXHD1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in LOXHD1 are known to be pathogenic (PMID: 19732867, 21465660, 25792669). -
Rare genetic deafness Pathogenic:1
The Gly768fs variant in LOXHD1 has not been previously identified in individuals with hearing loss and was absent from large population studies. This frameshift variant is predicted to alter the protein's amino acid sequence beginning at po sition 768 and lead to a premature termination codon 165 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Los s of function variants in the LOXHD1 gene have been previously reported to segre gate in affected individuals from several families with autosomal recessive nons yndromic hearing loss (Grillet 2009, Edvardson 2011). In summary, this variant m eets our criteria for pathogenicity (http://pcpgm.partners.org/LMM). -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at