rs201060702

Positions:

chr18-46522163-G-A

Variant summary

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

The NM_001384474.1(LOXHD1):c.5023C>T(p.Arg1675Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000985 in 1,551,604 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1675H) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0015 ( 1 hom., cov: 32)

Exomes 𝑓: 0.00093 ( 5 hom. )

Consequence

LOXHD1
NM_001384474.1 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:6

Conservation

PhyloP100: 1.05

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=0.00919342).

BP6

Variant 18-46522163-G-A is Benign according to our data. Variant chr18-46522163-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 178395.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Uncertain_significance=1, Benign=1}. Variant chr18-46522163-G-A is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00151 (230/152220) while in subpopulation AMR AF= 0.00673 (103/15296). AF 95% confidence interval is 0.00568. There are 1 homozygotes in gnomad4. There are 126 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LOXHD1	NM_001384474.1 linkuse as main transcript	c.5023C>T	p.Arg1675Cys	missense_variant	32/41	ENST00000642948.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LOXHD1	ENST00000642948.1 linkuse as main transcript	c.5023C>T	p.Arg1675Cys	missense_variant	32/41		NM_001384474.1	P1

Frequencies

GnomAD3 genomes

AF:

0.00151

AC:

230

AN:

152102

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000314

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00674

Gnomad ASJ

AF:

0.00490

Gnomad EAS

AF:

0.000579

Gnomad SAS

AF:

0.000832

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.00107

Gnomad OTH

AF:

0.00670

GnomAD3 exomes

AF:

0.00153

AC:

243

AN:

158452

Hom.:

AF XY:

0.00161

AC XY:

134

AN XY:

83472

show subpopulations

Gnomad AFR exome

AF:

0.000115

Gnomad AMR exome

AF:

0.00444

Gnomad ASJ exome

AF:

0.00424

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000966

Gnomad FIN exome

AF:

0.0000592

Gnomad NFE exome

AF:

0.000901

Gnomad OTH exome

AF:

0.00403

GnomAD4 exome

AF:

0.000928

AC:

1298

AN:

1399384

Hom.:

Cov.:

AF XY:

0.00100

AC XY:

690

AN XY:

690192

show subpopulations

Gnomad4 AFR exome

AF:

0.000222

Gnomad4 AMR exome

AF:

0.00389

Gnomad4 ASJ exome

AF:

0.00349

Gnomad4 EAS exome

AF:

0.0000560

Gnomad4 SAS exome

AF:

0.00101

Gnomad4 FIN exome

AF:

0.0000203

Gnomad4 NFE exome

AF:

0.000740

Gnomad4 OTH exome

AF:

0.00184

GnomAD4 genome

AF:

0.00151

AC:

230

AN:

152220

Hom.:

Cov.:

AF XY:

0.00169

AC XY:

126

AN XY:

74426

show subpopulations

Gnomad4 AFR

AF:

0.000313

Gnomad4 AMR

AF:

0.00673

Gnomad4 ASJ

AF:

0.00490

Gnomad4 EAS

AF:

0.000580

Gnomad4 SAS

AF:

0.000833

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00107

Gnomad4 OTH

AF:

0.00663

Alfa

AF:

0.00141

Hom.:

Bravo

AF:

0.00145

TwinsUK

AF:

0.00135

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00126

AC:

ExAC

AF:

0.00124

AC:

Asia WGS

AF:

0.000866

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:6

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:3

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	May 21, 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. -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2023	LOXHD1: BP4, BS2 -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

Autosomal recessive nonsyndromic hearing loss 77

Uncertain:1Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
Likely benign, no assertion criteria provided	clinical testing	Natera, Inc.	Dec 10, 2019	- -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Aug 03, 2017

p.Arg1675Cys in exon 32 of LOXHD1: This variant is not expected to have clinical significance due to a lack of conservation across species including mammals. Of note, more than 40 mammalian species have a cysteine (Cys) at this position des pite high nearby amino acid conservation. In addition, computational analyses do not suggest a high likelihood of impact to the protein. This variant has been i dentified in 0.13% (252/182290) of all chromosomes including 2 homozygotes with the highest frequencies in 0.44% (109/24794) of Latino chromosomes and 0.42% (36 /8536) of Ashkenazi Jewish chromosomes by the Genome Aggregation Database (gnomA D, http://gnomad.broadinstitute.org; dbSNP rs201060702). -

LOXHD1-related disorder

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 14, 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

0.060

BayesDel_addAF

Benign

-0.46

BayesDel_noAF

Benign

-0.43

CADD

Benign

DANN

Benign

0.89

DEOGEN2

Benign

0.057

.;.;T;.;.;.

Eigen

Benign

-0.48

Eigen_PC

Benign

-0.41

FATHMM_MKL

Benign

0.55

LIST_S2

Benign

0.83

T;T;T;T;T;T

M_CAP

Benign

0.057

MetaRNN

Benign

0.0092

T;T;T;T;T;T

MetaSVM

Benign

-0.64

MutationTaster

Benign

0.69

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

PrimateAI

Benign

0.27

PROVEAN

Benign

-0.39

.;N;.;N;.;.

REVEL

Benign

0.069

Sift

Benign

0.096

.;T;.;T;.;.

Sift4G

Uncertain

0.057

T;T;T;T;.;T

Polyphen

0.035

.;.;.;B;.;.

Vest4

0.14

MVP

0.31

ClinPred

0.015

GERP RS

2.6

Varity_R

0.081

gMVP

0.53

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.080

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