chr18-46529184-C-T
Variant summary
Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2
The NM_001384474.1(LOXHD1):c.4523G>A(p.Arg1508Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0003 in 1,551,572 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_001384474.1 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -9 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
LOXHD1 | NM_001384474.1 | c.4523G>A | p.Arg1508Lys | missense_variant | 29/41 | ENST00000642948.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
LOXHD1 | ENST00000642948.1 | c.4523G>A | p.Arg1508Lys | missense_variant | 29/41 | NM_001384474.1 | P1 |
Frequencies
GnomAD3 genomes AF: 0.000467 AC: 71AN: 152052Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000423 AC: 67AN: 158578Hom.: 0 AF XY: 0.000395 AC XY: 33AN XY: 83520
GnomAD4 exome AF: 0.000282 AC: 394AN: 1399402Hom.: 2 Cov.: 32 AF XY: 0.000274 AC XY: 189AN XY: 690204
GnomAD4 genome AF: 0.000467 AC: 71AN: 152170Hom.: 0 Cov.: 32 AF XY: 0.000524 AC XY: 39AN XY: 74378
ClinVar
Submissions by phenotype
Autosomal recessive nonsyndromic hearing loss 77 Uncertain:2
Uncertain significance, no assertion criteria provided | clinical testing | Natera, Inc. | Jan 08, 2020 | - - |
Uncertain significance, criteria provided, single submitter | 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. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Sep 19, 2022 | This sequence change replaces arginine, which is basic and polar, with lysine, which is basic and polar, at codon 1508 of the LOXHD1 protein (p.Arg1508Lys). This variant is present in population databases (rs199518750, gnomAD 0.08%). 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: 326840). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0". The lysine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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
Likely benign, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Oct 13, 2016 | p.Arg1508Lys in exon 29 of LOXHD1: This variant is not expected to have clinical significance due to a lack of conservation across species, including mammals. O f note, >10 mammals have a lysine (Lys) at this position despite high nearby ami no acid conservation. In addition, computational prediction tools do not suggest a high likelihood of impact to the protein. This variant has also been identifi ed in 5/8736 European chromosomes by the Exome Aggregation Consortium (ExAC, htt p://exac.broadinstitute.org; dbSNP rs199518750). - |
Inborn genetic diseases Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Sep 27, 2021 | This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at