rs61733519

Positions:

chr18-46505914-G-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_001384474.1(LOXHD1):c.5802C>A(p.Asn1934Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00399 in 1,551,990 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0031 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0041 ( 12 hom. )

Consequence

LOXHD1
NM_001384474.1 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:7

Conservation

PhyloP100: 2.61

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 -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0058615804).

BP6

Variant 18-46505914-G-T is Benign according to our data. Variant chr18-46505914-G-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 47946.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=5, Uncertain_significance=3}. Variant chr18-46505914-G-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00308 (469/152316) while in subpopulation AMR AF= 0.00562 (86/15312). AF 95% confidence interval is 0.00466. There are 1 homozygotes in gnomad4. There are 214 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 12 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LOXHD1	NM_001384474.1 linkuse as main transcript	c.5802C>A	p.Asn1934Lys	missense_variant	37/41	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.5802C>A	p.Asn1934Lys	missense_variant	37/41		NM_001384474.1	ENSP00000496347.1		A0A2R8Y7K4

Frequencies

GnomAD3 genomes

AF:

0.00308

AC:

469

AN:

152198

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000893

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00562

Gnomad ASJ

AF:

0.000864

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00245

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00450

Gnomad OTH

AF:

0.00526

GnomAD3 exomes

AF:

0.00278

AC:

439

AN:

157646

Hom.:

AF XY:

0.00244

AC XY:

203

AN XY:

83288

show subpopulations

Gnomad AFR exome

AF:

0.000739

Gnomad AMR exome

AF:

0.00441

Gnomad ASJ exome

AF:

0.000587

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00248

Gnomad NFE exome

AF:

0.00431

Gnomad OTH exome

AF:

0.00292

GnomAD4 exome

AF:

0.00409

AC:

5718

AN:

1399674

Hom.:

Cov.:

AF XY:

0.00385

AC XY:

2659

AN XY:

690322

show subpopulations

Gnomad4 AFR exome

AF:

0.00108

Gnomad4 AMR exome

AF:

0.00398

Gnomad4 ASJ exome

AF:

0.000357

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000252

Gnomad4 FIN exome

AF:

0.00190

Gnomad4 NFE exome

AF:

0.00484

Gnomad4 OTH exome

AF:

0.00358

GnomAD4 genome

AF:

0.00308

AC:

469

AN:

152316

Hom.:

Cov.:

AF XY:

0.00287

AC XY:

214

AN XY:

74486

show subpopulations

Gnomad4 AFR

AF:

0.000890

Gnomad4 AMR

AF:

0.00562

Gnomad4 ASJ

AF:

0.000864

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00245

Gnomad4 NFE

AF:

0.00450

Gnomad4 OTH

AF:

0.00521

Alfa

AF:

0.00389

Hom.:

Bravo

AF:

0.00315

TwinsUK

AF:

0.00566

AC:

ALSPAC

AF:

0.00467

AC:

ESP6500AA

AF:

0.00145

AC:

ESP6500EA

AF:

0.00691

AC:

ExAC

AF:

0.00183

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4Benign:7

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Autosomal recessive nonsyndromic hearing loss 77

Uncertain:2Benign:2

Uncertain significance, no assertion criteria provided	research	Division of Human Genetics, Children's Hospital of Philadelphia	Mar 20, 2015	This test identified a heterozygous variant (c.5616C>A;p.Asn1872Lys) in the LOXHD1 gene. This gene has been associated with an autosomal recessive form of hearing loss (DFNB77; MIM: 613079). This variant is considered a variant of unknown significance, as it has not been reported in literature; however, it was seen in 0.2% of individuals in ExAC. -
Likely benign, no assertion criteria provided	clinical testing	Natera, Inc.	Nov 11, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	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 did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 28, 2023	- -

not provided

Uncertain:1Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2023	LOXHD1: BP4 -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 31, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 30, 2018	- -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 17, 2023

The c.5616C>A (p.N1872K) alteration is located in exon 36 (coding exon 36) of the LOXHD1 gene. This alteration results from a C to A substitution at nucleotide position 5616, causing the asparagine (N) at amino acid position 1872 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Sep 14, 2017

p.Asn1872Lys in exon 36 of LOXHD1: This variant is not expected to have clinical significance because it has been identified in 0.4% (309/73462) of European chr omosomes, including 1 homozygous individual, by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs61733519). -

LOXHD1-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 26, 2020

This variant is classified as likely 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

0.16

BayesDel_addAF

Benign

-0.51

BayesDel_noAF

Benign

-0.50

CADD

Benign

DANN

Benign

0.95

DEOGEN2

Benign

0.019

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

Eigen

Benign

-0.25

Eigen_PC

Benign

-0.078

FATHMM_MKL

Uncertain

0.84

LIST_S2

Uncertain

0.93

D;D;D;D;D;D;D;D;D

M_CAP

Benign

0.012

MetaRNN

Benign

0.0059

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

MetaSVM

Benign

-0.97

PrimateAI

Benign

0.40

PROVEAN

Benign

-2.1

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

REVEL

Benign

0.050

Sift

Benign

0.052

T;.;D;.;T;T;.;.;T

Sift4G

Benign

0.60

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

Polyphen

0.0040

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

Vest4

0.21

MutPred

0.52

.;.;.;.;Gain of ubiquitination at N1872 (P = 0.0192);.;.;.;.;

MVP

0.21

ClinPred

0.027

GERP RS

2.5

Varity_R

0.085

gMVP

0.45

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