rs36086089

Variant names:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001384474.1(LOXHD1):c.2473G>A(p.Val825Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0852 in 1,522,664 control chromosomes in the GnomAD database, including 6,175 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.095 ( 803 hom., cov: 32)

Exomes 𝑓: 0.084 ( 5372 hom. )

Consequence

LOXHD1
NM_001384474.1 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 0.775

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]

LOXHD1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0016309619).

BP6

Variant 18-46563190-C-T is Benign according to our data. Variant chr18-46563190-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 47928.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr18-46563190-C-T is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.133 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LOXHD1	NM_001384474.1 link	c.2473G>A	p.Val825Met	missense_variant	Exon 18 of 41	ENST00000642948.1	NP_001371403.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
LOXHD1	ENST00000642948.1 link	c.2473G>A	p.Val825Met	missense_variant	Exon 18 of 41		NM_001384474.1	ENSP00000496347.1	A0A2R8Y7K4
LOXHD1	ENST00000536736.5 link	c.2473G>A	p.Val825Met	missense_variant	Exon 18 of 40	5		ENSP00000444586.1	F5GZB4
LOXHD1	ENST00000441551.6 link	c.2473G>A	p.Val825Met	missense_variant	Exon 18 of 39	5		ENSP00000387621.2	Q8IVV2-1
LOXHD1	ENST00000335730.6 link	n.1786G>A		non_coding_transcript_exon_variant	Exon 11 of 27	2

Frequencies

GnomAD3 genomes

AF:

0.0947

AC:

14394

AN:

152064

Hom.:

800

Cov.:

show subpopulations

Gnomad AFR

AF:

0.136

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0662

Gnomad ASJ

AF:

0.118

Gnomad EAS

AF:

0.00308

Gnomad SAS

AF:

0.125

Gnomad FIN

AF:

0.106

Gnomad MID

AF:

0.142

Gnomad NFE

AF:

0.0788

Gnomad OTH

AF:

0.0952

GnomAD3 exomes

AF:

0.0867

AC:

13685

AN:

157836

Hom.:

727

AF XY:

0.0918

AC XY:

7633

AN XY:

83168

show subpopulations

Gnomad AFR exome

AF:

0.138

Gnomad AMR exome

AF:

0.0516

Gnomad ASJ exome

AF:

0.122

Gnomad EAS exome

AF:

0.00319

Gnomad SAS exome

AF:

0.143

Gnomad FIN exome

AF:

0.0949

Gnomad NFE exome

AF:

0.0802

Gnomad OTH exome

AF:

0.0952

GnomAD4 exome

AF:

0.0841

AC:

115253

AN:

1370480

Hom.:

5372

Cov.:

AF XY:

0.0860

AC XY:

57601

AN XY:

670068

show subpopulations

Gnomad4 AFR exome

AF:

0.138

Gnomad4 AMR exome

AF:

0.0530

Gnomad4 ASJ exome

AF:

0.119

Gnomad4 EAS exome

AF:

0.00200

Gnomad4 SAS exome

AF:

0.141

Gnomad4 FIN exome

AF:

0.0954

Gnomad4 NFE exome

AF:

0.0799

Gnomad4 OTH exome

AF:

0.0923

GnomAD4 genome

AF:

0.0947

AC:

14413

AN:

152184

Hom.:

803

Cov.:

AF XY:

0.0947

AC XY:

7043

AN XY:

74398

show subpopulations

Gnomad4 AFR

AF:

0.136

Gnomad4 AMR

AF:

0.0661

Gnomad4 ASJ

AF:

0.118

Gnomad4 EAS

AF:

0.00308

Gnomad4 SAS

AF:

0.125

Gnomad4 FIN

AF:

0.106

Gnomad4 NFE

AF:

0.0788

Gnomad4 OTH

AF:

0.0938

Alfa

AF:

0.0833

Hom.:

813

Bravo

AF:

0.0933

TwinsUK

AF:

0.0704

AC:

261

ALSPAC

AF:

0.0778

AC:

300

ESP6500AA

AF:

0.140

AC:

194

ESP6500EA

AF:

0.0867

AC:

276

ExAC

AF:

0.101

AC:

2588

Asia WGS

AF:

0.0780

AC:

272

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Aug 03, 2017

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

May 07, 2012

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Val825Met in Exon 18 of LOXHD1: This variant is not expected to have clinical si gnificance because it has been identified in 14.1% (99/702) of African American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http: //evs.gs.washington.edu/EVS; dbSNP rs36086089). -

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 30, 2021

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Autosomal recessive nonsyndromic hearing loss 77

Benign:3

Sep 16, 2020

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jul 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided

Benign:2

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Benign

-0.57

BayesDel_noAF

Benign

-0.47

CADD

Benign

DANN

Benign

0.97

Eigen

Benign

-0.28

Eigen_PC

Benign

-0.19

FATHMM_MKL

Benign

0.44

LIST_S2

Benign

0.81

T;T;D

MetaRNN

Benign

0.0016

T;T;T

MetaSVM

Benign

-1.0

PrimateAI

Benign

0.44

PROVEAN

Benign

-1.7

N;.;.

REVEL

Benign

0.048

Sift

Benign

0.070

T;.;.

Sift4G

Benign

0.17

T;.;T

Polyphen

0.19

B;.;.

Vest4

0.099

ClinPred

0.0056

GERP RS

4.0

Varity_R

0.042

gMVP

0.34

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over