rs35088381

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_001384474.1(LOXHD1):c.1894G>T(p.Gly632Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0141 in 1,551,590 control chromosomes in the GnomAD database, including 267 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. G632S) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.015 ( 22 hom., cov: 32)

Exomes 𝑓: 0.014 ( 245 hom. )

Consequence

LOXHD1
NM_001384474.1 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:7

Conservation

PhyloP100: 7.84

Publications

11 publications found

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 Gene-Disease associations (from GenCC):

autosomal recessive nonsyndromic hearing loss 77
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, PanelApp Australia, Labcorp Genetics (formerly Invitae), Ambry Genetics
nonsyndromic genetic hearing loss
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
hearing loss, autosomal recessive
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
Fuchs' endothelial dystrophy
Inheritance: AD Classification: LIMITED Submitted by: Illumina

LOXHD1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.014604986).

BP6

Variant 18-46577783-C-A is Benign according to our data. Variant chr18-46577783-C-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 47923.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.0154 (2338/152196) while in subpopulation SAS AF = 0.0293 (141/4814). AF 95% confidence interval is 0.0254. There are 22 homozygotes in GnomAd4. There are 1113 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 22 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LOXHD1	NM_001384474.1 link	c.1894G>T	p.Gly632Cys	missense_variant	Exon 14 of 41	ENST00000642948.1	NP_001371403.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
LOXHD1	ENST00000642948.1 link	c.1894G>T	p.Gly632Cys	missense_variant	Exon 14 of 41		NM_001384474.1	ENSP00000496347.1
LOXHD1	ENST00000536736.5 link	c.1894G>T	p.Gly632Cys	missense_variant	Exon 14 of 40	5		ENSP00000444586.1
LOXHD1	ENST00000441551.6 link	c.1894G>T	p.Gly632Cys	missense_variant	Exon 14 of 39	5		ENSP00000387621.2
LOXHD1	ENST00000335730.6 link	n.1207G>T		non_coding_transcript_exon_variant	Exon 7 of 27	2

Frequencies

GnomAD3 genomes

AF:

0.0153

AC:

2334

AN:

152078

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0178

Gnomad AMI

AF:

0.0186

Gnomad AMR

AF:

0.0148

Gnomad ASJ

AF:

0.0476

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0295

Gnomad FIN

AF:

0.00499

Gnomad MID

AF:

0.0380

Gnomad NFE

AF:

0.0139

Gnomad OTH

AF:

0.0163

GnomAD2 exomes

AF:

0.0164

AC:

2600

AN:

158092

AF XY:

0.0179

show subpopulations

Gnomad AFR exome

AF:

0.0191

Gnomad AMR exome

AF:

0.0119

Gnomad ASJ exome

AF:

0.0456

Gnomad EAS exome

AF:

0.000265

Gnomad FIN exome

AF:

0.00308

Gnomad NFE exome

AF:

0.0134

Gnomad OTH exome

AF:

0.0186

GnomAD4 exome

AF:

0.0139

AC:

19482

AN:

1399394

Hom.:

245

Cov.:

AF XY:

0.0147

AC XY:

10151

AN XY:

690210

show subpopulations

African (AFR)

AF:

0.0195

AC:

617

AN:

31596

American (AMR)

AF:

0.0124

AC:

444

AN:

35704

Ashkenazi Jewish (ASJ)

AF:

0.0429

AC:

1081

AN:

25182

East Asian (EAS)

AF:

0.000168

AC:

AN:

35738

South Asian (SAS)

AF:

0.0350

AC:

2774

AN:

79232

European-Finnish (FIN)

AF:

0.00418

AC:

206

AN:

49276

Middle Eastern (MID)

AF:

0.0381

AC:

217

AN:

5696

European-Non Finnish (NFE)

AF:

0.0121

AC:

13078

AN:

1078968

Other (OTH)

AF:

0.0183

AC:

1059

AN:

58002

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.458

Heterozygous variant carriers

1055

2110

3166

4221

5276

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

510

1020

1530

2040

2550

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0154

AC:

2338

AN:

152196

Hom.:

Cov.:

AF XY:

0.0150

AC XY:

1113

AN XY:

74414

show subpopulations

African (AFR)

AF:

0.0179

AC:

743

AN:

41530

American (AMR)

AF:

0.0148

AC:

226

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.0476

AC:

165

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5172

South Asian (SAS)

AF:

0.0293

AC:

141

AN:

4814

European-Finnish (FIN)

AF:

0.00499

AC:

AN:

10612

Middle Eastern (MID)

AF:

0.0374

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0139

AC:

947

AN:

67996

Other (OTH)

AF:

0.0166

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

Heterozygous variant carriers

112

223

335

446

558

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

112

140

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0131

Hom.:

Bravo

AF:

0.0157

TwinsUK

AF:

0.0111

AC:

ALSPAC

AF:

0.0138

AC:

ESP6500AA

AF:

0.0152

AC:

ESP6500EA

AF:

0.0141

AC:

ExAC

AF:

0.0220

AC:

579

Asia WGS

AF:

0.0130

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:7

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Autosomal recessive nonsyndromic hearing loss 77

Uncertain:1Benign:3

Jul 10, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Sep 16, 2020

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

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, 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.

Nov 06, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

not specified

Benign:2

Dec 28, 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

Gly632Cys in Exon 14 of LOXHD1: This variant is not expected to have clinical si gnificance because it has been identified in 1.3% (33/2532) of European American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http ://evs.gs.washington.edu/EVS; dbSNP rs35088381).

not provided

Benign:2

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Aug 31, 2018

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.40

BayesDel_addAF

Benign

-0.0064

BayesDel_noAF

Pathogenic

0.24

CADD

Uncertain

(source)

DANN

Benign

0.96

DEOGEN2

Benign

0.0

.;.;.

Eigen

Uncertain

0.45

Eigen_PC

Uncertain

0.41

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.88

D;D;D

MetaRNN

Benign

0.015

T;T;T

MetaSVM

Uncertain

0.067

MutationAssessor

Benign

0.0

.;.;.

PhyloP100

7.8

PrimateAI

Uncertain

0.59

PROVEAN

Pathogenic

-6.8

D;.;.

REVEL

Uncertain

0.53

Sift

Uncertain

0.0030

D;.;.

Sift4G

Pathogenic

0.0010

D;.;D

Vest4

0.62

ClinPred

0.047

GERP RS

4.8

Varity_R

0.30

gMVP

0.82

Mutation Taster

=60/40

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over