rs61733519

Variant names:

Variant summary

Our verdict is Benign. The variant received -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. 16/21 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

Clinical Significance

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

Conservation

PhyloP100: 2.61

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=0.0058615804).

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 VariationId is 47946.

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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 12 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LOXHD1	NM_001384474.1 link	c.5802C>A	p.Asn1934Lys	missense_variant	Exon 37 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.5802C>A	p.Asn1934Lys	missense_variant	Exon 37 of 41		NM_001384474.1	ENSP00000496347.1

Frequencies

GnomAD3 genomes

AF:

0.00308

AC:

469

AN:

152198

Hom.:

Cov.:

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

GnomAD2 exomes

AF:

0.00278

AC:

439

AN:

157646

AF XY:

0.00244

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 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.:

Cov.:

AF XY:

0.00385

AC XY:

2659

AN XY:

690322

show subpopulations

African (AFR)

AF:

0.00108

AC:

AN:

31598

American (AMR)

AF:

0.00398

AC:

142

AN:

35704

Ashkenazi Jewish (ASJ)

AF:

0.000357

AC:

AN:

25182

East Asian (EAS)

AF:

0.00

AC:

AN:

35738

South Asian (SAS)

AF:

0.0000252

AC:

AN:

79236

European-Finnish (FIN)

AF:

0.00190

AC:

AN:

49390

Middle Eastern (MID)

AF:

0.000526

AC:

AN:

5700

European-Non Finnish (NFE)

AF:

0.00484

AC:

5226

AN:

1079030

Other (OTH)

AF:

0.00358

AC:

208

AN:

58096

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.463

Heterozygous variant carriers

328

657

985

1314

1642

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

200

400

600

800

1000

<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:

0.00308

AC:

469

AN:

152316

Hom.:

Cov.:

AF XY:

0.00287

AC XY:

214

AN XY:

74486

show subpopulations

African (AFR)

AF:

0.000890

AC:

AN:

41568

American (AMR)

AF:

0.00562

AC:

AN:

15312

Ashkenazi Jewish (ASJ)

AF:

0.000864

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5174

South Asian (SAS)

AF:

0.00

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.00245

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00450

AC:

306

AN:

68032

Other (OTH)

AF:

0.00521

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.491

Heterozygous variant carriers

107

134

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.00376

Hom.:

Bravo

AF:

0.00315

TwinsUK

AF:

0.00566

AC:

ALSPAC

AF:

0.00467

AC:

ESP6500AA

AF:

0.00145

AC:

ESP6500EA

AF:

0.00691

AC:

ExAC

AF:

0.00183

AC:

Asia WGS

AF:

0.000289

AC:

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

Sep 28, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 11, 2019

Natera, Inc.

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Mar 20, 2015

Division of Human Genetics, Children's Hospital of Philadelphia

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:research

This 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. -

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This 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. -

not provided

Uncertain:1Benign:3

Feb 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

LOXHD1: BP4, BS2 -

Mar 31, 2017

Eurofins Ntd Llc (ga)

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 30, 2018

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 27, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Inborn genetic diseases

Uncertain:1

Dec 17, 2023

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The 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

Sep 14, 2017

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

p.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

Oct 26, 2020

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

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: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Benign

-0.51

BayesDel_noAF

Benign

-0.50

CADD

Benign

(source)

DANN

Benign

0.95

DEOGEN2

Benign

0.019

.;.;.;T;.;.;.;T;.

Eigen

Benign

-0.25

Eigen_PC

Benign

-0.078

FATHMM_MKL

Uncertain

0.84

LIST_S2

Uncertain

0.93

D;D;D;D;D;D;D;D;D

M_CAP

Benign

0.012

MetaRNN

Benign

0.0059

T;T;T;T;T;T;T;T;T

MetaSVM

Benign

-0.97

PhyloP100

2.6

PrimateAI

Benign

0.40

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

GERP RS

2.5

Varity_R

0.085

gMVP

0.45

Mutation Taster

=97/3

polymorphism

(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