18-46522136-C-T
Variant summary
Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_StrongBP6
The NM_001384474.1(LOXHD1):c.5050G>A(p.Ala1684Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000117 in 1,551,288 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A1684G) has been classified as Likely benign.
Frequency
Consequence
NM_001384474.1 missense
Scores
Clinical Significance
Conservation
Publications
- autosomal recessive nonsyndromic hearing loss 77Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, PanelApp Australia, Labcorp Genetics (formerly Invitae), Ambry Genetics
- nonsyndromic genetic hearing lossInheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
- hearing loss, autosomal recessiveInheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
- Fuchs' endothelial dystrophyInheritance: AD Classification: LIMITED Submitted by: Illumina
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ACMG classification
Our verdict: Likely_benign. The variant received -5 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
LOXHD1 | NM_001384474.1 | c.5050G>A | p.Ala1684Thr | missense_variant | Exon 32 of 41 | ENST00000642948.1 | NP_001371403.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
LOXHD1 | ENST00000642948.1 | c.5050G>A | p.Ala1684Thr | missense_variant | Exon 32 of 41 | NM_001384474.1 | ENSP00000496347.1 |
Frequencies
GnomAD3 genomes AF: 0.000592 AC: 90AN: 152120Hom.: 1 Cov.: 32 show subpopulations
GnomAD2 exomes AF: 0.000152 AC: 24AN: 158026 AF XY: 0.0000841 show subpopulations
GnomAD4 exome AF: 0.0000650 AC: 91AN: 1399050Hom.: 0 Cov.: 31 AF XY: 0.0000681 AC XY: 47AN XY: 689998 show subpopulations
GnomAD4 genome AF: 0.000591 AC: 90AN: 152238Hom.: 1 Cov.: 32 AF XY: 0.000537 AC XY: 40AN XY: 74444 show subpopulations
ClinVar
Submissions by phenotype
Autosomal recessive nonsyndromic hearing loss 77 Uncertain:1
This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -
not provided Uncertain:1
This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 1684 of the LOXHD1 protein (p.Ala1684Thr). This variant is present in population databases (rs376122149, gnomAD 0.2%). This missense change has been observed in individual(s) with deafness (PMID: 35440622). ClinVar contains an entry for this variant (Variation ID: 227528). 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. 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. -
not specified Benign:1
p.Ala1684Thr in exon 32 of LOXHD1: This variant is not expected to have clinical significance because it has been identified in 0.4% (11/2680) of African chromo somes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs376122149). -
LOXHD1-related disorder Benign:1
This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at