rs753739358
Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PS1_ModeratePM1PM2PP5
The NM_182548.4(LHFPL5):c.472C>T(p.Arg158Trp) variant causes a missense change. The variant allele was found at a frequency of 0.000083 in 1,614,020 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely pathogenic in UniProt.
Frequency
Consequence
NM_182548.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 7 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000526 AC: 8AN: 152132Hom.: 0 Cov.: 31
GnomAD3 exomes AF: 0.0000597 AC: 15AN: 251400Hom.: 0 AF XY: 0.0000589 AC XY: 8AN XY: 135888
GnomAD4 exome AF: 0.0000862 AC: 126AN: 1461888Hom.: 1 Cov.: 32 AF XY: 0.0000853 AC XY: 62AN XY: 727242
GnomAD4 genome AF: 0.0000526 AC: 8AN: 152132Hom.: 0 Cov.: 31 AF XY: 0.0000404 AC XY: 3AN XY: 74306
ClinVar
Submissions by phenotype
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Mar 28, 2024 | This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 158 of the LHFPL5 protein (p.Arg158Trp). This variant is present in population databases (rs753739358, gnomAD 0.01%). This missense change has been observed in individual(s) with deafness (PMID: 30298622). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 505548). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. For these reasons, this variant has been classified as Pathogenic. - |
Deafness Pathogenic:1
Likely pathogenic, criteria provided, single submitter | research | Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital | Oct 04, 2024 | PP1,PM3(moderate),PM2,PP3 - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jan 24, 2017 | Variant classified as Uncertain Significance - Favor Pathogenic. The p.Arg158Trp variant in LHFPL5 has been previously reported in the homozygous state in an in dividual with congenital profound sensorineural hearing loss from a consanguineo us Arab family (Komara 2016). This variant has also been identified in 8/126732 European chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.b roadinstitute.org; dbSNP rs753739358). Although this variant has been seen in th e general population, its frequency is low enough to be consistent with the carr ier frequency for autosomal recessive hearing loss. However, population data spe cific for Arab populations are not available. Computational prediction tools and conservation analysis suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary , while there is some suspicion for a pathogenic role, the clinical significance of the p.Arg158Trp variant is uncertain. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at