rs140042576

Variant names:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS1

The NM_001384474.1(LOXHD1):c.4822G>A(p.Val1608Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000369 in 1,551,754 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V1608A) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0020 ( 1 hom., cov: 33)

Exomes 𝑓: 0.00019 ( 0 hom. )

Consequence

LOXHD1
NM_001384474.1 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1B:5

Conservation

PhyloP100: -0.991

Publications

2 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 -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0042520165).

BP6

Variant 18-46524520-C-T is Benign according to our data. Variant chr18-46524520-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 163902.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.002 (305/152340) while in subpopulation AFR AF = 0.00714 (297/41580). AF 95% confidence interval is 0.00648. There are 1 homozygotes in GnomAd4. There are 135 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LOXHD1	NM_001384474.1 link	c.4822G>A	p.Val1608Ile	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.4822G>A	p.Val1608Ile	missense_variant	Exon 31 of 41		NM_001384474.1	ENSP00000496347.1

Frequencies

GnomAD3 genomes

AF:

0.00196

AC:

299

AN:

152222

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00702

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000262

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.000955

GnomAD2 exomes

AF:

0.000588

AC:

AN:

158170

AF XY:

0.000420

show subpopulations

Gnomad AFR exome

AF:

0.00967

Gnomad AMR exome

AF:

0.000283

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000224

GnomAD4 exome

AF:

0.000192

AC:

268

AN:

1399414

Hom.:

Cov.:

AF XY:

0.000185

AC XY:

128

AN XY:

690216

show subpopulations

African (AFR)

AF:

0.00709

AC:

224

AN:

31598

American (AMR)

AF:

0.000308

AC:

AN:

35704

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25182

East Asian (EAS)

AF:

0.00

AC:

AN:

35738

South Asian (SAS)

AF:

0.0000631

AC:

AN:

79236

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49280

Middle Eastern (MID)

AF:

0.000176

AC:

AN:

5698

European-Non Finnish (NFE)

AF:

0.00000185

AC:

AN:

1078976

Other (OTH)

AF:

0.000431

AC:

AN:

58002

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.473

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

AF:

0.00200

AC:

305

AN:

152340

Hom.:

Cov.:

AF XY:

0.00181

AC XY:

135

AN XY:

74494

show subpopulations

African (AFR)

AF:

0.00714

AC:

297

AN:

41580

American (AMR)

AF:

0.000261

AC:

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

68034

Other (OTH)

AF:

0.000945

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

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:

0.00248

Hom.:

Bravo

AF:

0.00250

ESP6500AA

AF:

0.00361

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000936

AC:

Asia WGS

AF:

0.000866

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Uncertain:1Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Autosomal recessive nonsyndromic hearing loss 77

Uncertain:1Benign:1

Nov 01, 2017

Counsyl

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

Nov 11, 2019

Natera, Inc.

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not specified

Benign:2

Feb 26, 2016

Eurofins Ntd Llc (ga)

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 03, 2015

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

p.Val1608Ile in exon 31 of LOXHD1: This variant is not expected to have clinical significance because it has been identified in 0.8% (22/2752) of African chromo somes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs140042576). In addition, the valine (Val) at position 1608 is not cons erved across species, with several mammals having an isoleucine (Ile) at this po sition. -

not provided

Benign:1

Oct 04, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

LOXHD1-related disorder

Benign:1

Feb 03, 2021

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as 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

0.064

BayesDel_addAF

Benign

-0.71

BayesDel_noAF

Benign

-0.79

CADD

Benign

0.056

(source)

DANN

Benign

0.80

DEOGEN2

Benign

0.0022

.;.;T;.;.;.

Eigen

Benign

-1.6

Eigen_PC

Benign

-1.6

FATHMM_MKL

Benign

0.017

LIST_S2

Benign

0.75

T;T;T;T;T;T

M_CAP

Benign

0.0080

MetaRNN

Benign

0.0043

T;T;T;T;T;T

MetaSVM

Benign

-0.99

PhyloP100

-0.99

PrimateAI

Benign

0.29

PROVEAN

Benign

-0.10

.;N;.;N;.;.

REVEL

Benign

0.0070

Sift

Benign

0.48

.;T;.;T;.;.

Sift4G

Benign

0.21

T;T;T;T;.;T

Polyphen

0.034

.;.;.;B;.;.

Vest4

0.042

MVP

0.014

ClinPred

0.0050

GERP RS

-4.5

Varity_R

0.023

gMVP

0.13

Mutation Taster

=98/2

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