rs118174674

Positions:

chr18-46557437-C-T

Variant summary

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

The NM_001384474.1(LOXHD1):c.3269G>A(p.Arg1090Gln) variant causes a missense change. The variant allele was found at a frequency of 0.0175 in 1,552,130 control chromosomes in the GnomAD database, including 264 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 0.013 ( 19 hom., cov: 32)

Exomes 𝑓: 0.018 ( 245 hom. )

Consequence

LOXHD1
NM_001384474.1 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 5.03

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=0.013051391).

BP6

Variant 18-46557437-C-T is Benign according to our data. Variant chr18-46557437-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 47933.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, not_provided=1, Benign=6}.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0133 (2031/152252) while in subpopulation NFE AF= 0.0219 (1488/68022). AF 95% confidence interval is 0.021. There are 19 homozygotes in gnomad4. There are 910 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 19 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LOXHD1	NM_001384474.1 link	c.3269G>A	p.Arg1090Gln	missense_variant	21/41	ENST00000642948.1	NP_001371403.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LOXHD1	ENST00000642948.1 link	c.3269G>A	p.Arg1090Gln	missense_variant	21/41		NM_001384474.1	ENSP00000496347.1		A0A2R8Y7K4

Frequencies

GnomAD3 genomes

AF:

0.0134

AC:

2031

AN:

152134

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00304

Gnomad AMI

AF:

0.0186

Gnomad AMR

AF:

0.0154

Gnomad ASJ

AF:

0.0101

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00207

Gnomad FIN

AF:

0.00773

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.0219

Gnomad OTH

AF:

0.0163

GnomAD3 exomes

AF:

0.0122

AC:

1954

AN:

160138

Hom.:

AF XY:

0.0118

AC XY:

991

AN XY:

84018

show subpopulations

Gnomad AFR exome

AF:

0.00224

Gnomad AMR exome

AF:

0.00888

Gnomad ASJ exome

AF:

0.0104

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00211

Gnomad FIN exome

AF:

0.00719

Gnomad NFE exome

AF:

0.0224

Gnomad OTH exome

AF:

0.0140

GnomAD4 exome

AF:

0.0179

AC:

25077

AN:

1399878

Hom.:

245

Cov.:

AF XY:

0.0177

AC XY:

12249

AN XY:

690416

show subpopulations

Gnomad4 AFR exome

AF:

0.00241

Gnomad4 AMR exome

AF:

0.0106

Gnomad4 ASJ exome

AF:

0.0105

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00273

Gnomad4 FIN exome

AF:

0.00818

Gnomad4 NFE exome

AF:

0.0211

Gnomad4 OTH exome

AF:

0.0149

GnomAD4 genome

AF:

0.0133

AC:

2031

AN:

152252

Hom.:

Cov.:

AF XY:

0.0122

AC XY:

910

AN XY:

74444

show subpopulations

Gnomad4 AFR

AF:

0.00303

Gnomad4 AMR

AF:

0.0154

Gnomad4 ASJ

AF:

0.0101

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00208

Gnomad4 FIN

AF:

0.00773

Gnomad4 NFE

AF:

0.0219

Gnomad4 OTH

AF:

0.0161

Alfa

AF:

0.0194

Hom.:

Bravo

AF:

0.0141

TwinsUK

AF:

0.0197

AC:

ALSPAC

AF:

0.0252

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.0192

AC:

ExAC

AF:

0.00831

AC:

240

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:7Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Autosomal recessive nonsyndromic hearing loss 77

Uncertain:1Benign:2Other:1

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 01, 2023	- -
not provided, no classification provided	phenotyping only	GenomeConnect, ClinGen	-	Variant interpretted as Uncertain significance and reported on 07/21/2017 by GTR ID Shodair Children's Hospital. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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. -

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 29, 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. -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 07, 2012	Arg1090Gln in Exon 21 of LOXHD1: This variant is not expected to have clinical s ignificance because it has been identified in 2.1% (54/2532) of European America n chromosomes from a broad population by the NHLBI Exome Sequencing Project (htt p://evs.gs.washington.edu/EVS; dbSNP rs118174674). -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	May 16, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.30

BayesDel_addAF

Benign

-0.035

BayesDel_noAF

Pathogenic

0.20

CADD

Pathogenic

DANN

Uncertain

0.99

Eigen

Uncertain

0.61

Eigen_PC

Uncertain

0.61

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.97

D;D;D

MetaRNN

Benign

0.013

T;T;T

MetaSVM

Benign

-0.55

PrimateAI

Uncertain

0.52

PROVEAN

Uncertain

-2.5

D;.;.

REVEL

Uncertain

0.52

Sift

Uncertain

0.014

D;.;.

Sift4G

Uncertain

0.010

D;.;D

Polyphen

1.0

D;.;.

Vest4

0.60

ClinPred

0.037

GERP RS

5.2

Varity_R

0.11

gMVP

0.71

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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