rs61733519

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_001384474.1(LOXHD1):​c.5802C>A​(p.Asn1934Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00399 in 1,551,990 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0031 ( 1 hom., cov: 32)
Exomes 𝑓: 0.0041 ( 12 hom. )

Consequence

LOXHD1
NM_001384474.1 missense

Scores

2
16

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:7

Conservation

PhyloP100: 2.61
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.0058615804).
BP6
Variant 18-46505914-G-T is Benign according to our data. Variant chr18-46505914-G-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 47946.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=5, Uncertain_significance=3}. Variant chr18-46505914-G-T is described in Lovd as [Likely_benign].
BS1
Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00308 (469/152316) while in subpopulation AMR AF= 0.00562 (86/15312). AF 95% confidence interval is 0.00466. There are 1 homozygotes in gnomad4. There are 214 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
High Homozygotes in GnomAdExome4 at 12 AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
LOXHD1NM_001384474.1 linkuse as main transcriptc.5802C>A p.Asn1934Lys missense_variant 37/41 ENST00000642948.1 NP_001371403.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
LOXHD1ENST00000642948.1 linkuse as main transcriptc.5802C>A p.Asn1934Lys missense_variant 37/41 NM_001384474.1 ENSP00000496347.1 A0A2R8Y7K4

Frequencies

GnomAD3 genomes
AF:
0.00308
AC:
469
AN:
152198
Hom.:
1
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.000893
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00562
Gnomad ASJ
AF:
0.000864
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00245
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00450
Gnomad OTH
AF:
0.00526
GnomAD3 exomes
AF:
0.00278
AC:
439
AN:
157646
Hom.:
1
AF XY:
0.00244
AC XY:
203
AN XY:
83288
show subpopulations
Gnomad AFR exome
AF:
0.000739
Gnomad AMR exome
AF:
0.00441
Gnomad ASJ exome
AF:
0.000587
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00248
Gnomad NFE exome
AF:
0.00431
Gnomad OTH exome
AF:
0.00292
GnomAD4 exome
AF:
0.00409
AC:
5718
AN:
1399674
Hom.:
12
Cov.:
31
AF XY:
0.00385
AC XY:
2659
AN XY:
690322
show subpopulations
Gnomad4 AFR exome
AF:
0.00108
Gnomad4 AMR exome
AF:
0.00398
Gnomad4 ASJ exome
AF:
0.000357
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000252
Gnomad4 FIN exome
AF:
0.00190
Gnomad4 NFE exome
AF:
0.00484
Gnomad4 OTH exome
AF:
0.00358
GnomAD4 genome
AF:
0.00308
AC:
469
AN:
152316
Hom.:
1
Cov.:
32
AF XY:
0.00287
AC XY:
214
AN XY:
74486
show subpopulations
Gnomad4 AFR
AF:
0.000890
Gnomad4 AMR
AF:
0.00562
Gnomad4 ASJ
AF:
0.000864
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00245
Gnomad4 NFE
AF:
0.00450
Gnomad4 OTH
AF:
0.00521
Alfa
AF:
0.00389
Hom.:
1
Bravo
AF:
0.00315
TwinsUK
AF:
0.00566
AC:
21
ALSPAC
AF:
0.00467
AC:
18
ESP6500AA
AF:
0.00145
AC:
2
ESP6500EA
AF:
0.00691
AC:
22
ExAC
AF:
0.00183
AC:
48
Asia WGS
AF:
0.000289
AC:
1
AN:
3478

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:4Benign:7
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Autosomal recessive nonsyndromic hearing loss 77 Uncertain:2Benign:2
Uncertain significance, no assertion criteria providedresearchDivision of Human Genetics, Children's Hospital of PhiladelphiaMar 20, 2015This test identified a heterozygous variant (c.5616C>A;p.Asn1872Lys) in the LOXHD1 gene. This gene has been associated with an autosomal recessive form of hearing loss (DFNB77; MIM: 613079). This variant is considered a variant of unknown significance, as it has not been reported in literature; however, it was seen in 0.2% of individuals in ExAC. -
Likely benign, no assertion criteria providedclinical testingNatera, Inc.Nov 11, 2019- -
Uncertain significance, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaApr 27, 2017This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
Likely benign, criteria provided, single submitterclinical testingARUP Laboratories, Molecular Genetics and Genomics, ARUP LaboratoriesSep 28, 2023- -
not provided Uncertain:1Benign:3
Likely benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 31, 2024- -
Likely benign, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenMay 01, 2023LOXHD1: BP4 -
Uncertain significance, criteria provided, single submitterclinical testingEurofins Ntd Llc (ga)Mar 31, 2017- -
Likely benign, criteria provided, single submitterclinical testingGeneDxMar 30, 2018- -
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsDec 17, 2023The c.5616C>A (p.N1872K) alteration is located in exon 36 (coding exon 36) of the LOXHD1 gene. This alteration results from a C to A substitution at nucleotide position 5616, causing the asparagine (N) at amino acid position 1872 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -
not specified Benign:1
Likely benign, criteria provided, single submitterclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineSep 14, 2017p.Asn1872Lys in exon 36 of LOXHD1: This variant is not expected to have clinical significance because it has been identified in 0.4% (309/73462) of European chr omosomes, including 1 homozygous individual, by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs61733519). -
LOXHD1-related disorder Benign:1
Likely benign, no assertion criteria providedclinical testingPreventionGenetics, part of Exact SciencesOct 26, 2020This 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: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.16
BayesDel_addAF
Benign
-0.51
T
BayesDel_noAF
Benign
-0.50
CADD
Benign
22
DANN
Benign
0.95
DEOGEN2
Benign
0.019
.;.;.;T;.;.;.;T;.
Eigen
Benign
-0.25
Eigen_PC
Benign
-0.078
FATHMM_MKL
Uncertain
0.84
D
LIST_S2
Uncertain
0.93
D;D;D;D;D;D;D;D;D
M_CAP
Benign
0.012
T
MetaRNN
Benign
0.0059
T;T;T;T;T;T;T;T;T
MetaSVM
Benign
-0.97
T
PrimateAI
Benign
0.40
T
PROVEAN
Benign
-2.1
N;.;N;.;N;N;.;.;N
REVEL
Benign
0.050
Sift
Benign
0.052
T;.;D;.;T;T;.;.;T
Sift4G
Benign
0.60
T;T;T;T;T;T;.;T;.
Polyphen
0.0040
.;.;.;.;B;.;.;.;.
Vest4
0.21
MutPred
0.52
.;.;.;.;Gain of ubiquitination at N1872 (P = 0.0192);.;.;.;.;
MVP
0.21
ClinPred
0.027
T
GERP RS
2.5
Varity_R
0.085
gMVP
0.45

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs61733519; hg19: chr18-44085877; API