18-46534399-G-A

Position:

chr18-46534399-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001384474.1(LOXHD1):c.4148C>T(p.Thr1383Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00358 in 1,551,636 control chromosomes in the GnomAD database, including 180 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. T1383T) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.019 ( 90 hom., cov: 32)

Exomes 𝑓: 0.0019 ( 90 hom. )

Consequence

LOXHD1
NM_001384474.1 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 1.62

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.003362).

BP6

Variant 18-46534399-G-A is Benign according to our data. Variant chr18-46534399-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 47937.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0631 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LOXHD1	NM_001384474.1 linkuse as main transcript	c.4148C>T	p.Thr1383Met	missense_variant	27/41	ENST00000642948.1	NP_001371403.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LOXHD1	ENST00000642948.1 linkuse as main transcript	c.4148C>T	p.Thr1383Met	missense_variant	27/41		NM_001384474.1	ENSP00000496347	P1

Frequencies

GnomAD3 genomes

AF:

0.0190

AC:

2897

AN:

152084

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0652

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00995

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.000208

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000191

Gnomad OTH

AF:

0.0144

GnomAD3 exomes

AF:

0.00420

AC:

668

AN:

159010

Hom.:

AF XY:

0.00293

AC XY:

245

AN XY:

83696

show subpopulations

Gnomad AFR exome

AF:

0.0645

Gnomad AMR exome

AF:

0.00275

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000176

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000342

Gnomad OTH exome

AF:

0.00156

GnomAD4 exome

AF:

0.00190

AC:

2655

AN:

1399432

Hom.:

Cov.:

AF XY:

0.00162

AC XY:

1121

AN XY:

690218

show subpopulations

Gnomad4 AFR exome

AF:

0.0653

Gnomad4 AMR exome

AF:

0.00370

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000280

Gnomad4 SAS exome

AF:

0.000290

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000128

Gnomad4 OTH exome

AF:

0.00479

GnomAD4 genome

AF:

0.0191

AC:

2902

AN:

152204

Hom.:

Cov.:

AF XY:

0.0184

AC XY:

1373

AN XY:

74424

show subpopulations

Gnomad4 AFR

AF:

0.0651

Gnomad4 AMR

AF:

0.00994

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000191

Gnomad4 OTH

AF:

0.0143

Alfa

AF:

0.00230

Hom.:

Bravo

AF:

0.0223

ESP6500AA

AF:

0.0614

AC:

ESP6500EA

AF:

0.000943

AC:

ExAC

AF:

0.00731

AC:

193

Asia WGS

AF:

0.00318

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Nov 12, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 07, 2012	Thr1383Met in Exon 27 of LOXHD1: This variant is not expected to have clinical s ignificance because it has been identified in 6.7% (47/702) of African American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http: //evs.gs.washington.edu/EVS; dbSNP rs7244681). -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 16, 2018	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:2

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	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 and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Jun 15, 2020	- -

LOXHD1-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 19, 2019

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

0.086

BayesDel_addAF

Benign

-0.58

BayesDel_noAF

Benign

-0.56

CADD

Benign

DANN

Benign

0.74

DEOGEN2

Benign

0.019

.;.;T;.;.;.

Eigen

Benign

-0.39

Eigen_PC

Benign

-0.48

FATHMM_MKL

Benign

0.12

LIST_S2

Benign

0.82

T;T;T;T;T;T

MetaRNN

Benign

0.0034

T;T;T;T;T;T

MetaSVM

Benign

-1.1

MutationTaster

Benign

1.0

N;N;N;N;N;N;N

PrimateAI

Benign

0.37

PROVEAN

Benign

-1.0

.;N;.;N;.;.

REVEL

Benign

0.15

Sift

Benign

0.084

.;T;.;T;.;.

Sift4G

Benign

0.092

T;T;T;T;.;T

Polyphen

0.85

.;.;.;P;.;.

Vest4

0.13

MVP

0.11

ClinPred

0.013

GERP RS

4.4

Varity_R

0.019

gMVP

0.57

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over