chr6-35814627-C-T
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Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1PM2PP3_Moderate
The NM_182548.4(LHFPL5):c.494C>T(p.Thr165Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000116 in 1,614,022 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 Uncertain significance (★).
Frequency
Genomes: 𝑓 0.000092 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00012 ( 0 hom. )
Consequence
LHFPL5
NM_182548.4 missense
NM_182548.4 missense
Scores
10
7
1
Clinical Significance
Conservation
PhyloP100: 7.91
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 6 ACMG points.
PM1
In a topological_domain Extracellular (size 28) in uniprot entity LHPL5_HUMAN there are 5 pathogenic changes around while only 0 benign (100%) in NM_182548.4
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.856
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
LHFPL5 | NM_182548.4 | c.494C>T | p.Thr165Met | missense_variant | 2/4 | ENST00000360215.3 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
LHFPL5 | ENST00000360215.3 | c.494C>T | p.Thr165Met | missense_variant | 2/4 | 1 | NM_182548.4 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000920 AC: 14AN: 152130Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000517 AC: 13AN: 251392Hom.: 0 AF XY: 0.0000515 AC XY: 7AN XY: 135884
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GnomAD4 exome AF: 0.000118 AC: 173AN: 1461892Hom.: 0 Cov.: 32 AF XY: 0.000113 AC XY: 82AN XY: 727248
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GnomAD4 genome AF: 0.0000920 AC: 14AN: 152130Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74300
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ClinVar
Significance: Uncertain significance
Submissions summary: Pathogenic:2Uncertain:2
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Autosomal recessive nonsyndromic hearing loss 67 Pathogenic:2
Pathogenic, no assertion criteria provided | literature only | OMIM | Jul 01, 2006 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Dr.Nikuei Genetic Center | - | - - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jan 25, 2024 | In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 23217710, 27260575, 31835641, 16752389) - |
LHFPL5-related disorder Uncertain:1
Uncertain significance, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Dec 07, 2023 | The LHFPL5 c.494C>T variant is predicted to result in the amino acid substitution p.Thr165Met. This variant was reported in the homozygous state in six individuals from a consanguineous family with nonsyndromic hearing loss (Kalay. 2006. PubMed ID: 16752389). This variant is reported in 0.0096% of alleles in individuals of Ashkenazi Jewish descent in gnomAD. Although we suspect that this variant may be pathogenic, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Pathogenic
DEOGEN2
Pathogenic
D;D
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
.;D
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D;D
MetaSVM
Uncertain
D
MutationTaster
Benign
A;A
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D;.
REVEL
Pathogenic
Sift
Uncertain
D;.
Sift4G
Uncertain
D;.
Polyphen
D;D
Vest4
MVP
MPC
ClinPred
D
GERP RS
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Splicing
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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