rs370149278
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong
The NM_001384474.1(LOXHD1):āc.3673A>Gā(p.Ser1225Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000163 in 1,551,724 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Likely_benign. Variant got -2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
LOXHD1 | NM_001384474.1 | c.3673A>G | p.Ser1225Gly | missense_variant | 24/41 | ENST00000642948.1 | NP_001371403.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
LOXHD1 | ENST00000642948.1 | c.3673A>G | p.Ser1225Gly | missense_variant | 24/41 | NM_001384474.1 | ENSP00000496347.1 |
Frequencies
GnomAD3 genomes AF: 0.000881 AC: 134AN: 152170Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000182 AC: 29AN: 158922Hom.: 0 AF XY: 0.000108 AC XY: 9AN XY: 83682
GnomAD4 exome AF: 0.0000850 AC: 119AN: 1399436Hom.: 0 Cov.: 31 AF XY: 0.0000666 AC XY: 46AN XY: 690220
GnomAD4 genome AF: 0.000880 AC: 134AN: 152288Hom.: 0 Cov.: 32 AF XY: 0.000846 AC XY: 63AN XY: 74450
ClinVar
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jun 07, 2013 | Variant classified as Uncertain Significance - Favor Benign. The Ser1225Gly vari ant in LOXHD1 has not been reported in individuals with hearing loss, but has be en identified in 0.6% (9/1384) of African American chromosomes by the NHLBI Exom e Sequencing Project (http://evs.gs.washington.edu/EVS/). Although this variant has been seen in the general population, its frequency is not high enough to rul e out a pathogenic role. Computational analyses (biochemical amino acid properti es, conservation, AlignGVGD, PolyPhen2, and SIFT) do not provide strong support for or against an impact to the protein. In summary, the clinical significance o f this variant cannot be determined with certainty; however, based upon presence in the general population in the absence of any data to support a role in heari ng loss, we would lean towards a more likely benign role. - |
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jan 10, 2022 | The c.3673A>G (p.S1225G) alteration is located in exon 24 (coding exon 24) of the LOXHD1 gene. This alteration results from a A to G substitution at nucleotide position 3673, causing the serine (S) at amino acid position 1225 to be replaced by a glycine (G). 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 | Illumina Laboratory Services, Illumina | Jan 12, 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 Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 30, 2024 | - - |
LOXHD1-related disorder Benign:1
Likely benign, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Jun 12, 2023 | 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