rs12606417

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.4868A>G(p.Glu1623Gly) variant causes a missense change. The variant allele was found at a frequency of 0.0916 in 1,551,170 control chromosomes in the GnomAD database, including 7,016 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.071 ( 516 hom., cov: 33)

Exomes 𝑓: 0.094 ( 6500 hom. )

Consequence

LOXHD1
NM_001384474.1 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 4.34

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=0.0017565191).

BP6

Variant 18-46524474-T-C is Benign according to our data. Variant chr18-46524474-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 47941.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0983 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LOXHD1	NM_001384474.1 link	c.4868A>G	p.Glu1623Gly	missense_variant	Exon 31 of 41	ENST00000642948.1	NP_001371403.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LOXHD1	ENST00000642948.1 link	c.4868A>G	p.Glu1623Gly	missense_variant	Exon 31 of 41		NM_001384474.1	ENSP00000496347.1		A0A2R8Y7K4

Frequencies

GnomAD3 genomes

AF:

0.0712

AC:

10835

AN:

152190

Hom.:

516

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0227

Gnomad AMI

AF:

0.253

Gnomad AMR

AF:

0.0764

Gnomad ASJ

AF:

0.0934

Gnomad EAS

AF:

0.0594

Gnomad SAS

AF:

0.0738

Gnomad FIN

AF:

0.0444

Gnomad MID

AF:

0.0728

Gnomad NFE

AF:

0.100

Gnomad OTH

AF:

0.0937

GnomAD3 exomes

AF:

0.0767

AC:

12120

AN:

158082

Hom.:

561

AF XY:

0.0792

AC XY:

6592

AN XY:

83258

show subpopulations

Gnomad AFR exome

AF:

0.0233

Gnomad AMR exome

AF:

0.0530

Gnomad ASJ exome

AF:

0.0969

Gnomad EAS exome

AF:

0.0615

Gnomad SAS exome

AF:

0.0787

Gnomad FIN exome

AF:

0.0452

Gnomad NFE exome

AF:

0.101

Gnomad OTH exome

AF:

0.0900

GnomAD4 exome

AF:

0.0938

AC:

131206

AN:

1398862

Hom.:

6500

Cov.:

AF XY:

0.0938

AC XY:

64676

AN XY:

689818

show subpopulations

Gnomad4 AFR exome

AF:

0.0183

Gnomad4 AMR exome

AF:

0.0551

Gnomad4 ASJ exome

AF:

0.0955

Gnomad4 EAS exome

AF:

0.0396

Gnomad4 SAS exome

AF:

0.0800

Gnomad4 FIN exome

AF:

0.0486

Gnomad4 NFE exome

AF:

0.102

Gnomad4 OTH exome

AF:

0.0912

GnomAD4 genome

AF:

0.0711

AC:

10829

AN:

152308

Hom.:

516

Cov.:

AF XY:

0.0690

AC XY:

5140

AN XY:

74476

show subpopulations

Gnomad4 AFR

AF:

0.0226

Gnomad4 AMR

AF:

0.0763

Gnomad4 ASJ

AF:

0.0934

Gnomad4 EAS

AF:

0.0588

Gnomad4 SAS

AF:

0.0734

Gnomad4 FIN

AF:

0.0444

Gnomad4 NFE

AF:

0.100

Gnomad4 OTH

AF:

0.0927

Alfa

AF:

0.0965

Hom.:

1617

Bravo

AF:

0.0711

TwinsUK

AF:

0.103

AC:

381

ALSPAC

AF:

0.0986

AC:

380

ESP6500AA

AF:

0.0260

AC:

ESP6500EA

AF:

0.115

AC:

366

ExAC

AF:

0.0742

AC:

1881

Asia WGS

AF:

0.0590

AC:

204

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

May 09, 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

Glu1623Gly in Exon 31 of LOXHD1: This variant is not expected to have clinical s ignificance because it has been identified in 11.1% (281/2532) of European Ameri can chromosomes from a broad population by the NHLBI Exome Sequencing Project (h ttp://evs.gs.washington.edu/EVS; dbSNP rs12606417). -

PreventionGenetics, part of Exact Sciences

Significance: 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: Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

not provided

Benign:2

Feb 03, 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

0.14

BayesDel_addAF

Benign

-0.57

BayesDel_noAF

Benign

-0.50

CADD

Uncertain

DANN

Uncertain

0.98

DEOGEN2

Benign

0.074

.;.;T;.;.;T

Eigen

Benign

-0.0081

Eigen_PC

Benign

0.088

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.87

D;D;D;D;D;D

MetaRNN

Benign

0.0018

T;T;T;T;T;T

MetaSVM

Benign

-1.1

PrimateAI

Benign

0.38

PROVEAN

Uncertain

-3.1

.;D;.;D;.;.

REVEL

Benign

0.069

Sift

Benign

0.055

.;T;.;T;.;.

Sift4G

Uncertain

0.057

T;T;D;D;.;T

Polyphen

0.97

.;.;.;D;.;.

Vest4

0.19

ClinPred

0.034

GERP RS

5.1

Varity_R

0.65

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.

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