18-46477710-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001384474.1(LOXHD1):c.6584G>A(p.Arg2195His) variant causes a missense change. The variant allele was found at a frequency of 0.0625 in 1,551,918 control chromosomes in the GnomAD database, including 3,482 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. R2195R) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.047 ( 257 hom., cov: 33)

Exomes 𝑓: 0.064 ( 3225 hom. )

Consequence

LOXHD1
NM_001384474.1 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 5.02

Publications

15 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0019818544).

BP6

Variant 18-46477710-C-T is Benign according to our data. Variant chr18-46477710-C-T is described in ClinVar as Benign. ClinVar VariationId is 47951.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0693 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LOXHD1	NM_001384474.1 link	c.6584G>A	p.Arg2195His	missense_variant	Exon 41 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.6584G>A	p.Arg2195His	missense_variant	Exon 41 of 41		NM_001384474.1	ENSP00000496347.1		A0A2R8Y7K4

Frequencies

GnomAD3 genomes

AF:

0.0474

AC:

7212

AN:

152238

Hom.:

257

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0137

Gnomad AMI

AF:

0.182

Gnomad AMR

AF:

0.0599

Gnomad ASJ

AF:

0.0603

Gnomad EAS

AF:

0.000963

Gnomad SAS

AF:

0.0267

Gnomad FIN

AF:

0.0227

Gnomad MID

AF:

0.0380

Gnomad NFE

AF:

0.0709

Gnomad OTH

AF:

0.0664

GnomAD2 exomes

AF:

0.0482

AC:

7575

AN:

157258

AF XY:

0.0483

show subpopulations

Gnomad AFR exome

AF:

0.0132

Gnomad AMR exome

AF:

0.0447

Gnomad ASJ exome

AF:

0.0675

Gnomad EAS exome

AF:

0.00101

Gnomad FIN exome

AF:

0.0233

Gnomad NFE exome

AF:

0.0719

Gnomad OTH exome

AF:

0.0669

GnomAD4 exome

AF:

0.0641

AC:

89728

AN:

1399562

Hom.:

3225

Cov.:

AF XY:

0.0636

AC XY:

43869

AN XY:

690282

show subpopulations

African (AFR)

AF:

0.0102

AC:

321

AN:

31598

American (AMR)

AF:

0.0451

AC:

1609

AN:

35704

Ashkenazi Jewish (ASJ)

AF:

0.0672

AC:

1693

AN:

25182

East Asian (EAS)

AF:

0.000728

AC:

AN:

35738

South Asian (SAS)

AF:

0.0332

AC:

2632

AN:

79236

European-Finnish (FIN)

AF:

0.0239

AC:

1179

AN:

49342

Middle Eastern (MID)

AF:

0.0542

AC:

309

AN:

5698

European-Non Finnish (NFE)

AF:

0.0727

AC:

78438

AN:

1079018

Other (OTH)

AF:

0.0607

AC:

3521

AN:

58046

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

6330

12659

18989

25318

31648

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2886

5772

8658

11544

14430

<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:

0.0474

AC:

7217

AN:

152356

Hom.:

257

Cov.:

AF XY:

0.0449

AC XY:

3342

AN XY:

74508

show subpopulations

African (AFR)

AF:

0.0137

AC:

568

AN:

41596

American (AMR)

AF:

0.0599

AC:

916

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.0603

AC:

209

AN:

3464

East Asian (EAS)

AF:

0.000965

AC:

AN:

5182

South Asian (SAS)

AF:

0.0275

AC:

133

AN:

4830

European-Finnish (FIN)

AF:

0.0227

AC:

241

AN:

10624

Middle Eastern (MID)

AF:

0.0408

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0710

AC:

4828

AN:

68040

Other (OTH)

AF:

0.0658

AC:

139

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

373

747

1120

1494

1867

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

168

252

336

420

<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:

0.0617

Hom.:

725

Bravo

AF:

0.0483

TwinsUK

AF:

0.0731

AC:

271

ALSPAC

AF:

0.0688

AC:

265

ESP6500AA

AF:

0.0145

AC:

ESP6500EA

AF:

0.0798

AC:

254

ExAC

AF:

0.0426

AC:

1120

Asia WGS

AF:

0.0180

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 07, 2012

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Arg2133His in Exon 40 of LOXHD1: This variant is not expected to have clinical s ignificance because it has been identified in 7.7% (196/2532) of European Americ an chromosomes from a broad population by the NHLBI Exome Sequencing Project (ht tp://evs.gs.washington.edu/EVS; dbSNP rs74316327). -

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. -

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

- -

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Benign

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 was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

Jul 10, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.48

BayesDel_noAF

Benign

-0.41

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.049

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

Eigen

Benign

0.050

Eigen_PC

Benign

0.20

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Benign

0.80

T;T;T;D;D;D;D;D

MetaRNN

Benign

0.0020

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

MetaSVM

Benign

-1.1

PhyloP100

5.0

PrimateAI

Benign

0.39

PROVEAN

Uncertain

-3.4

D;.;D;.;D;D;.;.

REVEL

Benign

0.029

Sift

Benign

0.17

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

Sift4G

Benign

0.13

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

Polyphen

0.0040

.;.;.;.;B;.;.;.

Vest4

0.18

ClinPred

0.030

GERP RS

4.3

Varity_R

0.13

gMVP

0.30

Mutation Taster

=81/19

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