rs1377016

Positions:

Variant summary

Our verdict is Benign. Variant got -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. 14/18 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

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=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 id is 47949.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr18-46483635-G-A is described in Lovd as [Benign].

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/exons	MANE	Protein	UniProt
LOXHD1	NM_001384474.1 linkuse as main transcript	c.6293C>T	p.Ala2098Val	missense_variant	40/41	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.6293C>T	p.Ala2098Val	missense_variant	40/41		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

GnomAD3 exomes

AF:

0.368

AC:

57607

AN:

156616

Hom.:

11789

AF XY:

0.361

AC XY:

29927

AN XY:

82978

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 SAS exome

AF:

0.316

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

Gnomad4 AFR exome

AF:

0.196

Gnomad4 AMR exome

AF:

0.427

Gnomad4 ASJ exome

AF:

0.265

Gnomad4 EAS exome

AF:

0.770

Gnomad4 SAS exome

AF:

0.315

Gnomad4 FIN exome

AF:

0.365

Gnomad4 NFE exome

AF:

0.331

Gnomad4 OTH exome

AF:

0.336

GnomAD4 genome

AF:

0.314

AC:

47686

AN:

151840

Hom.:

8303

Cov.:

AF XY:

0.318

AC XY:

23566

AN XY:

74174

show subpopulations

Gnomad4 AFR

AF:

0.208

Gnomad4 AMR

AF:

0.384

Gnomad4 ASJ

AF:

0.247

Gnomad4 EAS

AF:

0.746

Gnomad4 SAS

AF:

0.323

Gnomad4 FIN

AF:

0.361

Gnomad4 NFE

AF:

0.327

Gnomad4 OTH

AF:

0.332

Alfa

AF:

0.328

Hom.:

20677

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

Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 07, 2012	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). -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 09, 2017	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. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

Autosomal recessive nonsyndromic hearing loss 77

Benign:3

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 10, 2021	- -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

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

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

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

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