rs118140267
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Variant summary
Our verdict is Benign. Variant got -15 ACMG points: 2P and 17B. PM2BP4_StrongBP6_Very_StrongBP7BS1
The NM_001384474.1(LOXHD1):c.2580G>A(p.Ala860=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000144 in 1,544,200 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 Likely benign (★★).
Frequency
Genomes: 𝑓 0.00033 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00012 ( 0 hom. )
Consequence
LOXHD1
NM_001384474.1 synonymous
NM_001384474.1 synonymous
Scores
2
Clinical Significance
Conservation
PhyloP100: -0.469
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 Benign. Variant got -15 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.72).
BP6
Variant 18-46563083-C-T is Benign according to our data. Variant chr18-46563083-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 227513.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BP7
Synonymous conserved (PhyloP=-0.469 with no splicing effect.
BS1
Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000335 (51/152284) while in subpopulation EAS AF= 0.00639 (33/5166). AF 95% confidence interval is 0.00467. There are 0 homozygotes in gnomad4. There are 29 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| LOXHD1 | NM_001384474.1 | c.2580G>A | p.Ala860= | synonymous_variant | 18/41 | ENST00000642948.1 | NP_001371403.1 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| LOXHD1 | ENST00000642948.1 | c.2580G>A | p.Ala860= | synonymous_variant | 18/41 | NM_001384474.1 | ENSP00000496347 | P1 | ||
| LOXHD1 | ENST00000536736.5 | c.2580G>A | p.Ala860= | synonymous_variant | 18/40 | 5 | ENSP00000444586 | |||
| LOXHD1 | ENST00000441551.6 | c.2580G>A | p.Ala860= | synonymous_variant | 18/39 | 5 | ENSP00000387621 | |||
| LOXHD1 | ENST00000335730.6 | n.1893G>A | non_coding_transcript_exon_variant | 11/27 | 2 |
Frequencies
GnomAD3 genomes 0.000322 AC: 49AN: 152166Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000505 AC: 80AN: 158436Hom.: 0 AF XY: 0.000503 AC XY: 42AN XY: 83446
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GnomAD4 exome AF: 0.000123 AC: 171AN: 1391916Hom.: 0 Cov.: 30 AF XY: 0.000131 AC XY: 90AN XY: 684738
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GnomAD4 genome 0.000335 AC: 51AN: 152284Hom.: 0 Cov.: 32 AF XY: 0.000390 AC XY: 29AN XY: 74448
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ClinVar
Significance: Benign/Likely benign
Submissions summary: Benign:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not specified Benign:1
| Likely benign, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Aug 12, 2015 | p.Ala860Ala in exon 18 of LOXHD1: This variant is not expected to have clinical significance because it does not alter an amino acid residue, is not located wit hin the splice consensus sequence, and has been identified in 1.2% (8/624) of Ea st Asian chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broa dinstitute.org; dbSNP rs118140267). - |
not provided Benign:1
| Benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 31, 2024 | - - |
Computational scores
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
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