18-46533320-G-A

Position:

chr18-46533320-G-A

Variant summary

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

The NM_001384474.1(LOXHD1):c.4217C>T(p.Ala1406Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00248 in 1,551,524 control chromosomes in the GnomAD database, including 30 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 0.0020 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0025 ( 30 hom. )

Consequence

LOXHD1
NM_001384474.1 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:9

Conservation

PhyloP100: 9.57

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=0.0068620443).

BP6

Variant 18-46533320-G-A is Benign according to our data. Variant chr18-46533320-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 178397.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Benign=6, Uncertain_significance=1}. Variant chr18-46533320-G-A is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00198 (301/152344) while in subpopulation SAS AF= 0.0164 (79/4820). AF 95% confidence interval is 0.0135. There are 0 homozygotes in gnomad4. There are 150 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 30 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LOXHD1	NM_001384474.1 linkuse as main transcript	c.4217C>T	p.Ala1406Val	missense_variant	28/41	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.4217C>T	p.Ala1406Val	missense_variant	28/41		NM_001384474.1	ENSP00000496347	P1

Frequencies

GnomAD3 genomes

AF:

0.00198

AC:

301

AN:

152226

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000289

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.00255

Gnomad ASJ

AF:

0.000864

Gnomad EAS

AF:

0.000385

Gnomad SAS

AF:

0.0166

Gnomad FIN

AF:

0.0000941

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.00226

Gnomad OTH

AF:

0.00239

GnomAD3 exomes

AF:

0.00399

AC:

634

AN:

158722

Hom.:

AF XY:

0.00493

AC XY:

411

AN XY:

83442

show subpopulations

Gnomad AFR exome

AF:

0.000227

Gnomad AMR exome

AF:

0.00211

Gnomad ASJ exome

AF:

0.00118

Gnomad EAS exome

AF:

0.0000884

Gnomad SAS exome

AF:

0.0168

Gnomad FIN exome

AF:

0.000355

Gnomad NFE exome

AF:

0.00269

Gnomad OTH exome

AF:

0.00335

GnomAD4 exome

AF:

0.00253

AC:

3546

AN:

1399180

Hom.:

Cov.:

AF XY:

0.00297

AC XY:

2053

AN XY:

690102

show subpopulations

Gnomad4 AFR exome

AF:

0.000602

Gnomad4 AMR exome

AF:

0.00211

Gnomad4 ASJ exome

AF:

0.000755

Gnomad4 EAS exome

AF:

0.0000280

Gnomad4 SAS exome

AF:

0.0158

Gnomad4 FIN exome

AF:

0.000142

Gnomad4 NFE exome

AF:

0.00176

Gnomad4 OTH exome

AF:

0.00336

GnomAD4 genome

AF:

0.00198

AC:

301

AN:

152344

Hom.:

Cov.:

AF XY:

0.00201

AC XY:

150

AN XY:

74498

show subpopulations

Gnomad4 AFR

AF:

0.000289

Gnomad4 AMR

AF:

0.00255

Gnomad4 ASJ

AF:

0.000864

Gnomad4 EAS

AF:

0.000386

Gnomad4 SAS

AF:

0.0164

Gnomad4 FIN

AF:

0.0000941

Gnomad4 NFE

AF:

0.00226

Gnomad4 OTH

AF:

0.00284

Alfa

AF:

0.00206

Hom.:

Bravo

AF:

0.00215

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.000778

AC:

ESP6500AA

AF:

0.000723

AC:

ESP6500EA

AF:

0.00189

AC:

ExAC

AF:

0.00686

AC:

179

Asia WGS

AF:

0.00520

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:9

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Autosomal recessive nonsyndromic hearing loss 77

Uncertain:2Benign:3

Benign, criteria provided, single submitter	clinical testing	Pars Genome Lab	May 18, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Counsyl	Mar 06, 2017	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Jan 09, 2020	- -
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. -
Uncertain significance, no assertion criteria provided	clinical testing	Baylor Genetics	Jan 29, 2016	Our laboratory reported dual molecular diagnoses in PUF60 (NM_001271099.1, c.1381-2A>G) and LOXHD1 (NM_144612.6, c.4217C>T and c.442A>T in trans) in one individual with reported features which include delayed motor milestones, delayed speech, intellectual disability, bilateral sensorineural hearing loss, febrile seizures, dysmorphic features, short stature, failure to thrive, and abnormal visual tracking. Heterozygotes for the LOXHD1 variants would not be expected to be affected. -

not specified

Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 26, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jan 20, 2015	p.Ala1406Val in exon 28 LOXHD1: This variant is not expected to have clinical si gnificance because it has been identified in 1.9% (148/7908) of South Asian chro mosomes with 5 homozygotes by the Exome Aggregation Consortium (ExAC, http://exa c.broadinstitute.org; dbSNP rs146739496). -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2024	LOXHD1: BP4, BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 04, 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Benign

-0.53

BayesDel_noAF

Benign

-0.51

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.020

.;.;T;.;.;T

Eigen

Uncertain

0.22

Eigen_PC

Uncertain

0.41

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.89

D;D;D;D;D;D

MetaRNN

Benign

0.0069

T;T;T;T;T;T

MetaSVM

Benign

-0.77

MutationTaster

Benign

0.99

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

PrimateAI

Benign

0.29

PROVEAN

Benign

-2.0

.;N;.;N;.;.

REVEL

Benign

0.22

Sift

Uncertain

0.029

.;D;.;D;.;.

Sift4G

Uncertain

0.034

D;D;D;D;.;D

Polyphen

0.91

.;.;.;P;.;.

Vest4

0.053

MVP

0.21

ClinPred

0.079

GERP RS

5.5

Varity_R

0.11

gMVP

0.47

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