18-46477797-G-C
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Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate
The NM_001384474.1(LOXHD1):āc.6497C>Gā(p.Pro2166Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0000425 in 1,551,732 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā ā ).
Frequency
Genomes: š 0.000013 ( 0 hom., cov: 32)
Exomes š: 0.000046 ( 0 hom. )
Consequence
LOXHD1
NM_001384474.1 missense
NM_001384474.1 missense
Scores
3
15
Clinical Significance
Conservation
PhyloP100: 3.94
Genes affected
LOXHD1 (HGNC:26521): (lipoxygenase homology PLAT domains 1) This gene encodes a highly conserved protein consisting entirely of PLAT (polycystin/lipoxygenase/alpha-toxin) domains, thought to be involved in targeting proteins to the plasma membrane. Studies in mice show that this gene is expressed in the mechanosensory hair cells in the inner ear, and mutations in this gene lead to auditory defects, indicating that this gene is essential for normal hair cell function. Screening of human families segregating deafness identified a mutation in this gene which causes DFNB77, a progressive form of autosomal-recessive nonsyndromic hearing loss (ARNSHL). Alternatively spliced transcript variants encoding different isoforms have been noted for this gene. [provided by RefSeq, Mar 2010]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 0 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.17691365).
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
LOXHD1 | NM_001384474.1 | c.6497C>G | p.Pro2166Arg | missense_variant | 41/41 | ENST00000642948.1 | NP_001371403.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
LOXHD1 | ENST00000642948.1 | c.6497C>G | p.Pro2166Arg | missense_variant | 41/41 | NM_001384474.1 | ENSP00000496347.1 |
Frequencies
GnomAD3 genomes AF: 0.0000131 AC: 2AN: 152250Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000255 AC: 4AN: 156768Hom.: 0 AF XY: 0.0000120 AC XY: 1AN XY: 83056
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GnomAD4 exome AF: 0.0000457 AC: 64AN: 1399482Hom.: 0 Cov.: 31 AF XY: 0.0000420 AC XY: 29AN XY: 690256
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GnomAD4 genome AF: 0.0000131 AC: 2AN: 152250Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74390
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Aug 19, 2024 | The c.6311C>G (p.P2104R) alteration is located in exon 40 (coding exon 40) of the LOXHD1 gene. This alteration results from a C to G substitution at nucleotide position 6311, causing the proline (P) at amino acid position 2104 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Autosomal recessive nonsyndromic hearing loss 77 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Jan 27, 2017 | - - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Aug 16, 2022 | This sequence change replaces proline, which is neutral and non-polar, with arginine, which is basic and polar, at codon 2104 of the LOXHD1 protein (p.Pro2104Arg). This variant is present in population databases (no rsID available, gnomAD 0.005%). This variant has not been reported in the literature in individuals affected with LOXHD1-related conditions. ClinVar contains an entry for this variant (Variation ID: 547922). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
DEOGEN2
Benign
.;.;.;T;.;.;.;.
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;D;D;T;T;T;T;T
M_CAP
Benign
T
MetaRNN
Benign
T;T;T;T;T;T;T;T
MetaSVM
Benign
T
PrimateAI
Uncertain
T
PROVEAN
Benign
N;.;N;.;N;N;.;.
REVEL
Benign
Sift
Benign
T;.;T;.;T;T;.;.
Sift4G
Benign
T;T;T;T;T;T;.;T
Polyphen
0.013
.;.;.;.;B;.;.;.
Vest4
MutPred
0.63
.;.;.;.;Gain of methylation at P2104 (P = 0.0104);.;.;.;
MVP
ClinPred
T
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gMVP
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