rs199847981

Positions:

chr18-46560146-G-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001384474.1(LOXHD1):c.2998C>T(p.Arg1000Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000841 in 1,372,566 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00069 ( 0 hom., cov: 31)

Exomes 𝑓: 0.00086 ( 0 hom. )

Consequence

LOXHD1
NM_001384474.1 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:7

Conservation

PhyloP100: 1.73

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 Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.0525434).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LOXHD1	NM_001384474.1 linkuse as main transcript	c.2998C>T	p.Arg1000Trp	missense_variant	19/41	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.2998C>T	p.Arg1000Trp	missense_variant	19/41		NM_001384474.1	ENSP00000496347.1	A0A2R8Y7K4
LOXHD1	ENST00000536736.5 linkuse as main transcript	c.2998C>T	p.Arg1000Trp	missense_variant	19/40	5		ENSP00000444586.1	F5GZB4
LOXHD1	ENST00000441551.6 linkuse as main transcript	c.2599-2657C>T		intron_variant		5		ENSP00000387621.2	Q8IVV2-1
LOXHD1	ENST00000335730.6 linkuse as main transcript	n.2311C>T		non_coding_transcript_exon_variant	12/27	2

Frequencies

GnomAD3 genomes

AF:

0.000681

AC:

AN:

138096

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000186

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000811

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:

0.00131

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000530

AC:

AN:

158366

Hom.:

AF XY:

0.000431

AC XY:

AN XY:

83432

show subpopulations

Gnomad AFR exome

AF:

0.000230

Gnomad AMR exome

AF:

0.0000404

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000132

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00125

Gnomad OTH exome

AF:

0.000447

GnomAD4 exome

AF:

0.000858

AC:

1059

AN:

1234382

Hom.:

Cov.:

AF XY:

0.000873

AC XY:

529

AN XY:

606190

show subpopulations

Gnomad4 AFR exome

AF:

0.000188

Gnomad4 AMR exome

AF:

0.0000329

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000478

Gnomad4 SAS exome

AF:

0.000270

Gnomad4 FIN exome

AF:

0.000137

Gnomad4 NFE exome

AF:

0.00103

Gnomad4 OTH exome

AF:

0.000533

GnomAD4 genome

AF:

0.000687

AC:

AN:

138184

Hom.:

Cov.:

AF XY:

0.000499

AC XY:

AN XY:

66160

show subpopulations

Gnomad4 AFR

AF:

0.000186

Gnomad4 AMR

AF:

0.0000809

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00133

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000975

Hom.:

Bravo

AF:

0.000544

TwinsUK

AF:

0.00108

AC:

ALSPAC

AF:

0.00156

AC:

ESP6500AA

AF:

0.000723

AC:

ESP6500EA

AF:

0.000629

AC:

ExAC

AF:

0.000273

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Autosomal recessive nonsyndromic hearing loss 77

Uncertain:3

Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Jan 12, 2022	- -
Uncertain significance, flagged submission	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. -

not provided

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 23, 2022	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 1000 of the LOXHD1 protein (p.Arg1000Trp). This variant is present in population databases (rs199847981, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with nonsyndromic deafness (PMID: 27068579). ClinVar contains an entry for this variant (Variation ID: 449913). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Aug 24, 2017	The R1000W variant in the LOXHD1 gene has been reported previously with another LOXHD1 variant in an individual with autosomal recessive nonsyndromic hearing loss (Sommen et al., 2016). However, it was unknown if the two variants were on the same LOXHD1 allele (in cis) or on opposite alleles (in trans), and this individual was also reported to have two variants that were thought to be causative in another hearing loss gene (Sommen et al., 2016). The R1000W variant is observed in 8/8,596 (0.09%) alleles from individuals of European (non-Finnish) background in the ExAC dataset (Lek et al., 2016). The R1000W variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. While this substitution occurs at a position that is not conserved, in silico analysis predicts this variant is probably damaging to the protein structure/function. We interpret R1000W as a variant of uncertain significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Oct 14, 2022	The LOXHD1 c.2998C>T (p.Arg1000Trp) missense variant results in the substitution of arginine at amino acid position 1000 with tryptophan. This variant has been reported in one study in which the variant was found in a compound heterozygous state with a second allele in LOXHD1 in an individual with hearing loss who also carried two alleles in TECTA, which is also associated with nonsyndromic hearing loss (PMID: 27068579). The c.2998C>T variant has been reported at a frequency of 0.001207 in the European (non-Finnish) population of the Genome Aggregation Database (version 2.1.1). Based on available evidence, the c.2998C>T (p.Arg1000Trp) variant is classified as a variant of uncertain significance for nonsyndromic genetic hearing loss. -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Feb 19, 2019

Variant classified as Uncertain Significance - Favor Benign. The p.Arg1000Trp variant in LOXHD1 has been previously identified in 2 individuals with hearing loss (Sommen 2016, LMM data); however one of these individuals harbored two additional variants in the TECTA gene that were thought to be responsible for their hearing loss (Sommen 2016). This variant has also been identified in 0.1% (92/76204) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). Computational prediction tools and conservation analysis do not provide strong support for or against an impact to the protein. In summary, while the clinical significance of the p.Arg1000Trp variant is uncertain, its frequency suggests it is more likely to be benign. ACMG/AMP Criteria applied: BS1_Supporting. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.45

BayesDel_noAF

Benign

-0.44

CADD

Pathogenic

DANN

Pathogenic

1.0

Eigen

Uncertain

0.36

Eigen_PC

Uncertain

0.34

FATHMM_MKL

Uncertain

0.85

LIST_S2

Uncertain

0.93

D;D

M_CAP

Uncertain

0.14

MetaRNN

Benign

0.053

T;T

MetaSVM

Benign

-1.2

PrimateAI

Benign

0.38

PROVEAN

Uncertain

-4.1

D;.

REVEL

Benign

0.14

Sift

Uncertain

0.0050

D;.

Sift4G

Pathogenic

0.0010

D;.

Polyphen

1.0

D;.

Vest4

0.49

MVP

0.33

ClinPred

0.12

GERP RS

3.2

gMVP

0.56

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