rs35088381

Positions:

Variant summary

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

The NM_001384474.1(LOXHD1):c.1894G>T(p.Gly632Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0141 in 1,551,590 control chromosomes in the GnomAD database, including 267 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.015 ( 22 hom., cov: 32)

Exomes 𝑓: 0.014 ( 245 hom. )

Consequence

LOXHD1
NM_001384474.1 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:7

Conservation

PhyloP100: 7.84

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=0.014604986).

BP6

Variant 18-46577783-C-A is Benign according to our data. Variant chr18-46577783-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 47923.We mark this variant Likely_benign, oryginal submissions are: {Benign=6, Uncertain_significance=1}. Variant chr18-46577783-C-A is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0154 (2338/152196) while in subpopulation SAS AF= 0.0293 (141/4814). AF 95% confidence interval is 0.0254. There are 22 homozygotes in gnomad4. There are 1113 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 22 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LOXHD1	NM_001384474.1 linkuse as main transcript	c.1894G>T	p.Gly632Cys	missense_variant	14/41	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.1894G>T	p.Gly632Cys	missense_variant	14/41		NM_001384474.1	ENSP00000496347	P1
LOXHD1	ENST00000536736.5 linkuse as main transcript	c.1894G>T	p.Gly632Cys	missense_variant	14/40	5		ENSP00000444586
LOXHD1	ENST00000441551.6 linkuse as main transcript	c.1894G>T	p.Gly632Cys	missense_variant	14/39	5		ENSP00000387621		Q8IVV2-1
LOXHD1	ENST00000335730.6 linkuse as main transcript	n.1207G>T		non_coding_transcript_exon_variant	7/27	2

Frequencies

GnomAD3 genomes

AF:

0.0153

AC:

2334

AN:

152078

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0178

Gnomad AMI

AF:

0.0186

Gnomad AMR

AF:

0.0148

Gnomad ASJ

AF:

0.0476

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0295

Gnomad FIN

AF:

0.00499

Gnomad MID

AF:

0.0380

Gnomad NFE

AF:

0.0139

Gnomad OTH

AF:

0.0163

GnomAD3 exomes

AF:

0.0164

AC:

2600

AN:

158092

Hom.:

AF XY:

0.0179

AC XY:

1488

AN XY:

83300

show subpopulations

Gnomad AFR exome

AF:

0.0191

Gnomad AMR exome

AF:

0.0119

Gnomad ASJ exome

AF:

0.0456

Gnomad EAS exome

AF:

0.000265

Gnomad SAS exome

AF:

0.0352

Gnomad FIN exome

AF:

0.00308

Gnomad NFE exome

AF:

0.0134

Gnomad OTH exome

AF:

0.0186

GnomAD4 exome

AF:

0.0139

AC:

19482

AN:

1399394

Hom.:

245

Cov.:

AF XY:

0.0147

AC XY:

10151

AN XY:

690210

show subpopulations

Gnomad4 AFR exome

AF:

0.0195

Gnomad4 AMR exome

AF:

0.0124

Gnomad4 ASJ exome

AF:

0.0429

Gnomad4 EAS exome

AF:

0.000168

Gnomad4 SAS exome

AF:

0.0350

Gnomad4 FIN exome

AF:

0.00418

Gnomad4 NFE exome

AF:

0.0121

Gnomad4 OTH exome

AF:

0.0183

GnomAD4 genome

AF:

0.0154

AC:

2338

AN:

152196

Hom.:

Cov.:

AF XY:

0.0150

AC XY:

1113

AN XY:

74414

show subpopulations

Gnomad4 AFR

AF:

0.0179

Gnomad4 AMR

AF:

0.0148

Gnomad4 ASJ

AF:

0.0476

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.0293

Gnomad4 FIN

AF:

0.00499

Gnomad4 NFE

AF:

0.0139

Gnomad4 OTH

AF:

0.0166

Alfa

AF:

0.0127

Hom.:

Bravo

AF:

0.0157

TwinsUK

AF:

0.0111

AC:

ALSPAC

AF:

0.0138

AC:

ESP6500AA

AF:

0.0152

AC:

ESP6500EA

AF:

0.0141

AC:

ExAC

AF:

0.0220

AC:

579

Asia WGS

AF:

0.0130

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:7

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Autosomal recessive nonsyndromic hearing loss 77

Uncertain:1Benign:3

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 06, 2023	- -
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. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 10, 2021	- -

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 07, 2012	Gly632Cys in Exon 14 of LOXHD1: This variant is not expected to have clinical si gnificance because it has been identified in 1.3% (33/2532) of European American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http ://evs.gs.washington.edu/EVS; dbSNP rs35088381). -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 28, 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. -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Aug 31, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.40

BayesDel_addAF

Benign

-0.0064

BayesDel_noAF

Pathogenic

0.24

CADD

Uncertain

DANN

Benign

0.96

Eigen

Uncertain

0.45

Eigen_PC

Uncertain

0.41

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.88

D;D;D

MetaRNN

Benign

0.015

T;T;T

MetaSVM

Uncertain

0.067

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Uncertain

0.59

PROVEAN

Pathogenic

-6.8

D;.;.

REVEL

Uncertain

0.53

Sift

Uncertain

0.0030

D;.;.

Sift4G

Pathogenic

0.0010

D;.;D

Polyphen

1.0

D;.;.

Vest4

0.62

ClinPred

0.047

GERP RS

4.8

Varity_R

0.30

gMVP

0.82

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