rs143142227

Positions:

chr18-46591970-C-T

Variant summary

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

The NM_001384474.1(LOXHD1):c.1617G>A(p.Met539Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000277 in 1,552,012 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/18 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 0.0016 ( 2 hom., cov: 32)

Exomes 𝑓: 0.00014 ( 0 hom. )

Consequence

LOXHD1
NM_001384474.1 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:5

Conservation

PhyloP100: 0.956

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:

LOXHD1 (HGNC:):

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=0.007528752).

BP6

Variant 18-46591970-C-T is Benign according to our data. Variant chr18-46591970-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 163929.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=2, Benign=1}.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00158 (240/152328) while in subpopulation AFR AF= 0.00548 (228/41568). AF 95% confidence interval is 0.0049. There are 2 homozygotes in gnomad4. There are 110 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LOXHD1	NM_001384474.1 linkuse as main transcript	c.1617G>A	p.Met539Ile	missense_variant	12/41	ENST00000642948.1	NP_001371403.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
LOXHD1	ENST00000642948.1 linkuse as main transcript	c.1617G>A	p.Met539Ile	missense_variant	12/41		NM_001384474.1	ENSP00000496347.1	A0A2R8Y7K4
LOXHD1	ENST00000536736.5 linkuse as main transcript	c.1617G>A	p.Met539Ile	missense_variant	12/40	5		ENSP00000444586.1	F5GZB4
LOXHD1	ENST00000441551.6 linkuse as main transcript	c.1617G>A	p.Met539Ile	missense_variant	12/39	5		ENSP00000387621.2	Q8IVV2-1
LOXHD1	ENST00000335730.6 linkuse as main transcript	n.930G>A		non_coding_transcript_exon_variant	5/27	2

Frequencies

GnomAD3 genomes

AF:

0.00158

AC:

240

AN:

152210

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00550

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000720

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000300

AC:

AN:

160000

Hom.:

AF XY:

0.000167

AC XY:

AN XY:

83932

show subpopulations

Gnomad AFR exome

AF:

0.00477

Gnomad AMR exome

AF:

0.000161

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000220

GnomAD4 exome

AF:

0.000136

AC:

190

AN:

1399684

Hom.:

Cov.:

AF XY:

0.000119

AC XY:

AN XY:

690338

show subpopulations

Gnomad4 AFR exome

AF:

0.00513

Gnomad4 AMR exome

AF:

0.000112

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.000413

GnomAD4 genome

AF:

0.00158

AC:

240

AN:

152328

Hom.:

Cov.:

AF XY:

0.00148

AC XY:

110

AN XY:

74494

show subpopulations

Gnomad4 AFR

AF:

0.00548

Gnomad4 AMR

AF:

0.000719

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.000278

Hom.:

Bravo

AF:

0.00195

ESP6500AA

AF:

0.00867

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000818

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

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.	Nov 22, 2019	- -

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jun 21, 2016	p.Met539Ile in exon 12 of LOXHD1: This variant is not expected to have clinical significance because it has been identified in 0.7% (20/2898) of African chromos omes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs143142227) -
Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 12, 2016	- -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 10, 2022

The c.1617G>A (p.M539I) alteration is located in exon 12 (coding exon 12) of the LOXHD1 gene. This alteration results from a G to A substitution at nucleotide position 1617, causing the methionine (M) at amino acid position 539 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 29, 2024

- -

LOXHD1-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 01, 2021

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

Pathogenic

0.77

BayesDel_addAF

Benign

-0.63

BayesDel_noAF

Benign

-0.68

CADD

Benign

DANN

Uncertain

0.98

Eigen

Benign

-0.50

Eigen_PC

Benign

-0.23

FATHMM_MKL

Uncertain

0.77

LIST_S2

Benign

0.85

T;T;T

M_CAP

Benign

0.013

MetaRNN

Benign

0.0075

T;T;T

MetaSVM

Benign

-0.90

PrimateAI

Uncertain

0.56

PROVEAN

Benign

-0.57

N;.;.

REVEL

Benign

0.055

Sift

Benign

0.23

T;.;.

Sift4G

Benign

0.30

T;.;T

Polyphen

0.0030

B;.;.

Vest4

0.21

MutPred

0.52

Loss of catalytic residue at M539 (P = 0.0601);Loss of catalytic residue at M539 (P = 0.0601);Loss of catalytic residue at M539 (P = 0.0601);

MVP

0.030

ClinPred

0.021

GERP RS

3.1

Varity_R

0.25

gMVP

0.40

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