chr6-35805755-T-TG
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Variant summary
Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PVS1_StrongPM2PP5_Moderate
The NM_182548.4(LHFPL5):c.89dup(p.Thr31TyrfsTer41) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,890 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★).
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000014 ( 0 hom. )
Consequence
LHFPL5
NM_182548.4 frameshift
NM_182548.4 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 9.93
Genes affected
LHFPL5 (HGNC:21253): (LHFPL tetraspan subfamily member 5) This gene is a member of the lipoma HMGIC fusion partner (LHFP) gene family, which is a subset of the superfamily of tetraspan transmembrane protein encoding genes. Mutations in this gene result in deafness in humans, and a mutation in a similar gene in mice results in deafness and vestibular dysfunction with severe degeneration of the organ of Corti. It is proposed to function in hair bundle morphogenesis. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 8 ACMG points.
PVS1
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 12 pathogenic variants in the truncated region.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 6-35805755-T-TG is Pathogenic according to our data. Variant chr6-35805755-T-TG is described in ClinVar as [Likely_pathogenic]. Clinvar id is 667378.Status of the report is criteria_provided_single_submitter, 1 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
LHFPL5 | NM_182548.4 | c.89dup | p.Thr31TyrfsTer41 | frameshift_variant | 1/4 | ENST00000360215.3 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
LHFPL5 | ENST00000360215.3 | c.89dup | p.Thr31TyrfsTer41 | frameshift_variant | 1/4 | 1 | NM_182548.4 | P1 | |
LHFPL5 | ENST00000651132.1 | c.89dup | p.Thr31TyrfsTer41 | frameshift_variant | 4/7 | P1 | |||
LHFPL5 | ENST00000651676.1 | c.89dup | p.Thr31TyrfsTer41 | frameshift_variant | 1/4 | P1 | |||
LHFPL5 | ENST00000651994.1 | c.89dup | p.Thr31TyrfsTer41 | frameshift_variant, NMD_transcript_variant | 1/4 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 genomes
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GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251488Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135920
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GnomAD4 exome AF: 0.00000137 AC: 2AN: 1461890Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 727246
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GnomAD4 genome Cov.: 32
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ClinVar
Significance: Likely pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Rare genetic deafness Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Apr 17, 2018 | The p.Thr31fs was identified in the homozygous state one individual from a consa nguineous family with sensorineural hearing loss and segregated with disease in 3 affected relatives (Bensaid 2011). It was also identified in 1/111712 of Europ ean chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadi nstitute.org; dbSNP rs756030149). This variant is predicted to cause a frameshif t, which alters the protein?s amino acid sequence beginning at position 31 and l eads to a premature termination codon 41 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. In summary, althoug h additional studies are required to fully establish its clinical significance, the p.Thr31fs variant is likely pathogenic. ACMG/AMP Criteria applied: PVS1_Stro ng; PP1; PM2. - |
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at