rs199847981
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Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong
The NM_001384474.1(LOXHD1):c.2998C>T(p.Arg1000Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000841 in 1,372,566 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Genomes: 𝑓 0.00069 ( 0 hom., cov: 31)
Exomes 𝑓: 0.00086 ( 0 hom. )
Consequence
LOXHD1
NM_001384474.1 missense
NM_001384474.1 missense
Scores
2
7
7
Clinical Significance
Conservation
PhyloP100: 1.73
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 Likely_benign. Variant got -2 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.0525434).
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
LOXHD1 | NM_001384474.1 | c.2998C>T | p.Arg1000Trp | missense_variant | 19/41 | ENST00000642948.1 | NP_001371403.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
LOXHD1 | ENST00000642948.1 | c.2998C>T | p.Arg1000Trp | missense_variant | 19/41 | NM_001384474.1 | ENSP00000496347.1 | |||
LOXHD1 | ENST00000536736.5 | c.2998C>T | p.Arg1000Trp | missense_variant | 19/40 | 5 | ENSP00000444586.1 | |||
LOXHD1 | ENST00000441551.6 | c.2599-2657C>T | intron_variant | 5 | ENSP00000387621.2 | |||||
LOXHD1 | ENST00000335730.6 | n.2311C>T | non_coding_transcript_exon_variant | 12/27 | 2 |
Frequencies
GnomAD3 genomes AF: 0.000681 AC: 94AN: 138096Hom.: 0 Cov.: 31
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GnomAD3 exomes AF: 0.000530 AC: 84AN: 158366Hom.: 0 AF XY: 0.000431 AC XY: 36AN XY: 83432
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GnomAD4 exome AF: 0.000858 AC: 1059AN: 1234382Hom.: 0 Cov.: 38 AF XY: 0.000873 AC XY: 529AN XY: 606190
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GnomAD4 genome AF: 0.000687 AC: 95AN: 138184Hom.: 0 Cov.: 31 AF XY: 0.000499 AC XY: 33AN XY: 66160
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:7
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Autosomal recessive nonsyndromic hearing loss 77 Uncertain:3
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Jan 12, 2022 | - - |
Uncertain significance, flagged submission | clinical testing | Illumina Laboratory Services, Illumina | Jan 13, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. - |
Uncertain significance, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
not provided Uncertain:3
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Oct 14, 2022 | The LOXHD1 c.2998C>T (p.Arg1000Trp) missense variant results in the substitution of arginine at amino acid position 1000 with tryptophan. This variant has been reported in one study in which the variant was found in a compound heterozygous state with a second allele in LOXHD1 in an individual with hearing loss who also carried two alleles in TECTA, which is also associated with nonsyndromic hearing loss (PMID: 27068579). The c.2998C>T variant has been reported at a frequency of 0.001207 in the European (non-Finnish) population of the Genome Aggregation Database (version 2.1.1). Based on available evidence, the c.2998C>T (p.Arg1000Trp) variant is classified as a variant of uncertain significance for nonsyndromic genetic hearing loss. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Feb 23, 2022 | This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 1000 of the LOXHD1 protein (p.Arg1000Trp). This variant is present in population databases (rs199847981, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with nonsyndromic deafness (PMID: 27068579). ClinVar contains an entry for this variant (Variation ID: 449913). 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: "Deleterious"; PolyPhen-2: "Probably 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Aug 24, 2017 | The R1000W variant in the LOXHD1 gene has been reported previously with another LOXHD1 variant in an individual with autosomal recessive nonsyndromic hearing loss (Sommen et al., 2016). However, it was unknown if the two variants were on the same LOXHD1 allele (in cis) or on opposite alleles (in trans), and this individual was also reported to have two variants that were thought to be causative in another hearing loss gene (Sommen et al., 2016). The R1000W variant is observed in 8/8,596 (0.09%) alleles from individuals of European (non-Finnish) background in the ExAC dataset (Lek et al., 2016). The R1000W variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. While this substitution occurs at a position that is not conserved, in silico analysis predicts this variant is probably damaging to the protein structure/function. We interpret R1000W as a variant of uncertain significance. - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Feb 19, 2019 | Variant classified as Uncertain Significance - Favor Benign. The p.Arg1000Trp variant in LOXHD1 has been previously identified in 2 individuals with hearing loss (Sommen 2016, LMM data); however one of these individuals harbored two additional variants in the TECTA gene that were thought to be responsible for their hearing loss (Sommen 2016). This variant has also been identified in 0.1% (92/76204) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). Computational prediction tools and conservation analysis do not provide strong support for or against an impact to the protein. In summary, while the clinical significance of the p.Arg1000Trp variant is uncertain, its frequency suggests it is more likely to be benign. ACMG/AMP Criteria applied: BS1_Supporting. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Pathogenic
DANN
Pathogenic
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;D
M_CAP
Uncertain
D
MetaRNN
Benign
T;T
MetaSVM
Benign
T
PrimateAI
Benign
T
PROVEAN
Uncertain
D;.
REVEL
Benign
Sift
Uncertain
D;.
Sift4G
Pathogenic
D;.
Polyphen
D;.
Vest4
MVP
ClinPred
T
GERP RS
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