rs191697915
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong
The NM_001384474.1(LOXHD1):c.722A>G(p.Asn241Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000416 in 1,551,698 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts 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. N241K) has been classified as Uncertain significance.
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 | UniProt |
---|---|---|---|---|---|---|---|
LOXHD1 | NM_001384474.1 | c.722A>G | p.Asn241Ser | missense_variant | 6/41 | ENST00000642948.1 | |
LOXHD1 | NM_144612.7 | c.722A>G | p.Asn241Ser | missense_variant | 6/40 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
LOXHD1 | ENST00000642948.1 | c.722A>G | p.Asn241Ser | missense_variant | 6/41 | NM_001384474.1 | P1 | ||
LOXHD1 | ENST00000536736.5 | c.722A>G | p.Asn241Ser | missense_variant | 6/40 | 5 | |||
LOXHD1 | ENST00000441551.6 | c.722A>G | p.Asn241Ser | missense_variant | 6/39 | 5 |
Frequencies
GnomAD3 genomes ? AF: 0.000420 AC: 64AN: 152208Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000415 AC: 65AN: 156600Hom.: 0 AF XY: 0.000386 AC XY: 32AN XY: 82970
GnomAD4 exome AF: 0.000415 AC: 581AN: 1399372Hom.: 1 Cov.: 30 AF XY: 0.000391 AC XY: 270AN XY: 690178
GnomAD4 genome ? AF: 0.000420 AC: 64AN: 152326Hom.: 0 Cov.: 32 AF XY: 0.000483 AC XY: 36AN XY: 74476
ClinVar
Submissions by phenotype
not provided Uncertain:4
Uncertain significance, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Feb 01, 2023 | LOXHD1: PM2 - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jul 08, 2022 | This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 241 of the LOXHD1 protein (p.Asn241Ser). This variant is present in population databases (rs191697915, gnomAD 0.2%). 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: 198278). 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: "Benign"; Align-GVGD: "Class C0"). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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 | Eurofins Ntd Llc (ga) | Oct 16, 2014 | - - |
Uncertain significance, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The LOXHD1 p.Asn241Ser variant was not identified in the literature nor was it identified in LOVD 3.0. The variant was identified in dbSNP (ID: rs191697915) and ClinVar (classified as uncertain significance by EGL Genetics and Laboratory for Molecular Medicine). The variant was identified in control databases in 73 of 187990 chromosomes at a frequency of 0.0003883 (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: Latino in 40 of 25514 chromosomes (freq: 0.001568), Other in 5 of 5484 chromosomes (freq: 0.000912), Ashkenazi Jewish in 7 of 8790 chromosomes (freq: 0.000796) and European (non-Finnish) in 21 of 76012 chromosomes (freq: 0.000276), but was not observed in the African, East Asian, European (Finnish), or South Asian populations. The p.Asn241 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and three of four in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. - |
Autosomal recessive nonsyndromic hearing loss 77 Uncertain:2
Uncertain significance, no assertion criteria provided | clinical testing | Natera, Inc. | Nov 11, 2019 | - - |
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 specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Nov 27, 2018 | The p.Asn241Ser variant in LOXHD1 has been previously reported by our laboratory in 1 individual with hearing loss. It has also been identified in 0.15% (40/255 14) of Latino chromosomes by gnomAD (http://gnomad.broadinstitute.org), and has been reported in ClinVar (Variation ID 198278). Computational prediction tools a nd conservation analysis suggest that the variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summar y, the clinical significance of the p.Asn241Ser variant is uncertain. ACMG/AMP c riteria: BS1_Supporting, PP3. - |
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Aug 10, 2021 | The c.722A>G (p.N241S) alteration is located in exon 6 (coding exon 6) of the LOXHD1 gene. This alteration results from a A to G substitution at nucleotide position 722, causing the asparagine (N) at amino acid position 241 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
LOXHD1-related disorder Benign:1
Likely benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Apr 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