NM_001384474.1:c.6293C>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.6293C>T(p.Ala2098Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.338 in 1,551,192 control chromosomes in the GnomAD database, including 93,793 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.31 ( 8303 hom., cov: 31)

Exomes 𝑓: 0.34 ( 85490 hom. )

Consequence

LOXHD1
NM_001384474.1 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: 0.643

Publications

34 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=1.0759802E-5).

BP6

Variant 18-46483635-G-A is Benign according to our data. Variant chr18-46483635-G-A is described in ClinVar as Benign. ClinVar VariationId is 47949.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.726 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LOXHD1	NM_001384474.1 link	c.6293C>T	p.Ala2098Val	missense_variant	Exon 40 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.6293C>T	p.Ala2098Val	missense_variant	Exon 40 of 41		NM_001384474.1	ENSP00000496347.1		A0A2R8Y7K4

Frequencies

GnomAD3 genomes

AF:

0.314

AC:

47617

AN:

151722

Hom.:

8286

Cov.:

show subpopulations

Gnomad AFR

AF:

0.207

Gnomad AMI

AF:

0.230

Gnomad AMR

AF:

0.384

Gnomad ASJ

AF:

0.247

Gnomad EAS

AF:

0.747

Gnomad SAS

AF:

0.321

Gnomad FIN

AF:

0.361

Gnomad MID

AF:

0.212

Gnomad NFE

AF:

0.327

Gnomad OTH

AF:

0.329

GnomAD2 exomes

AF:

0.368

AC:

57607

AN:

156616

AF XY:

0.361

show subpopulations

Gnomad AFR exome

AF:

0.211

Gnomad AMR exome

AF:

0.443

Gnomad ASJ exome

AF:

0.259

Gnomad EAS exome

AF:

0.742

Gnomad FIN exome

AF:

0.373

Gnomad NFE exome

AF:

0.326

Gnomad OTH exome

AF:

0.337

GnomAD4 exome

AF:

0.341

AC:

477016

AN:

1399352

Hom.:

85490

Cov.:

AF XY:

0.340

AC XY:

234630

AN XY:

690170

show subpopulations

African (AFR)

AF:

0.196

AC:

6193

AN:

31600

American (AMR)

AF:

0.427

AC:

15242

AN:

35704

Ashkenazi Jewish (ASJ)

AF:

0.265

AC:

6669

AN:

25182

East Asian (EAS)

AF:

0.770

AC:

27527

AN:

35734

South Asian (SAS)

AF:

0.315

AC:

24929

AN:

79234

European-Finnish (FIN)

AF:

0.365

AC:

17964

AN:

49282

Middle Eastern (MID)

AF:

0.240

AC:

1369

AN:

5696

European-Non Finnish (NFE)

AF:

0.331

AC:

357640

AN:

1078908

Other (OTH)

AF:

0.336

AC:

19483

AN:

58012

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.465

Heterozygous variant carriers

17845

35690

53536

71381

89226

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

11832

23664

35496

47328

59160

<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:

0.314

AC:

47686

AN:

151840

Hom.:

8303

Cov.:

AF XY:

0.318

AC XY:

23566

AN XY:

74174

show subpopulations

African (AFR)

AF:

0.208

AC:

8606

AN:

41436

American (AMR)

AF:

0.384

AC:

5868

AN:

15266

Ashkenazi Jewish (ASJ)

AF:

0.247

AC:

855

AN:

3460

East Asian (EAS)

AF:

0.746

AC:

3836

AN:

5142

South Asian (SAS)

AF:

0.323

AC:

1541

AN:

4768

European-Finnish (FIN)

AF:

0.361

AC:

3801

AN:

10540

Middle Eastern (MID)

AF:

0.207

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.327

AC:

22210

AN:

67916

Other (OTH)

AF:

0.332

AC:

699

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1587

3174

4762

6349

7936

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

470

940

1410

1880

2350

<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:

0.324

Hom.:

29386

Bravo

AF:

0.315

TwinsUK

AF:

0.319

AC:

1181

ALSPAC

AF:

0.333

AC:

1283

ExAC

AF:

0.300

AC:

7619

Asia WGS

AF:

0.483

AC:

1675

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

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

Ala2036Val in Exon 39 of LOXHD1: This variant is not expected to have clinical s ignificance because it has been identified in 33.0% (836/2532) of European Ameri can chromosomes from a broad population by the NHLBI Exome Sequencing Project (h ttp://evs.gs.washington.edu/EVS; dbSNP rs1377016). -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

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

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

0.061

BayesDel_addAF

Benign

-0.71

BayesDel_noAF

Benign

-0.64

CADD

Benign

(source)

DANN

Benign

0.93

DEOGEN2

Benign

0.0087

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

Eigen

Benign

-0.72

Eigen_PC

Benign

-0.52

FATHMM_MKL

Benign

0.16

LIST_S2

Benign

0.036

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

MetaRNN

Benign

0.000011

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

MetaSVM

Benign

-0.95

PhyloP100

0.64

PrimateAI

Benign

0.45

PROVEAN

Benign

0.38

N;.;N;.;N;N;.;.

REVEL

Benign

0.063

Sift

Benign

0.54

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

Sift4G

Benign

0.50

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

Polyphen

0.0

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

Vest4

0.029

ClinPred

0.0017

GERP RS

3.2

Varity_R

0.036

gMVP

0.17

Mutation Taster

=100/0

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