rs546893082

Positions:

chr18-46577833-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_001384474.1(LOXHD1):c.1844G>A(p.Arg615Gln) variant causes a missense change. The variant allele was found at a frequency of 0.0000458 in 1,551,660 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R615W) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000059 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000044 ( 0 hom. )

Consequence

LOXHD1
NM_001384474.1 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:4

Conservation

PhyloP100: 4.72

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 Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.3099951).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LOXHD1	NM_001384474.1 linkuse as main transcript	c.1844G>A	p.Arg615Gln	missense_variant	14/41	ENST00000642948.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LOXHD1	ENST00000642948.1 linkuse as main transcript	c.1844G>A	p.Arg615Gln	missense_variant	14/41		NM_001384474.1	P1
LOXHD1	ENST00000536736.5 linkuse as main transcript	c.1844G>A	p.Arg615Gln	missense_variant	14/40	5
LOXHD1	ENST00000441551.6 linkuse as main transcript	c.1844G>A	p.Arg615Gln	missense_variant	14/39	5			Q8IVV2-1
LOXHD1	ENST00000335730.6 linkuse as main transcript	n.1157G>A		non_coding_transcript_exon_variant	7/27	2

Frequencies

GnomAD3 genomes

AF:

0.0000592

AC:

AN:

152114

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00116

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000442

AC:

AN:

158200

Hom.:

AF XY:

0.0000360

AC XY:

AN XY:

83322

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000404

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000177

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000658

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000443

AC:

AN:

1399428

Hom.:

Cov.:

AF XY:

0.0000377

AC XY:

AN XY:

690218

show subpopulations

Gnomad4 AFR exome

AF:

0.0000633

Gnomad4 AMR exome

AF:

0.0000280

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000476

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000343

Gnomad4 OTH exome

AF:

0.0000862

GnomAD4 genome

AF:

0.0000591

AC:

AN:

152232

Hom.:

Cov.:

AF XY:

0.0000672

AC XY:

AN XY:

74424

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00116

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000508

Hom.:

Bravo

AF:

0.0000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Autosomal recessive nonsyndromic hearing loss 77

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jun 10, 2021	- -
Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jul 26, 2013

The Arg615Gln variant in LOXHD1 has not been reported in individuals with hearin g loss or in large population studies. Computational analyses (biochemical amino acid properties, conservation, AlignGVGD, PolyPhen2, and SIFT) do not provide s trong support for or against an impact to the protein. In summary, additional da ta is needed to determine the clinical significance of this variant. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Oct 13, 2022

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 615 of the LOXHD1 protein (p.Arg615Gln). This variant is present in population databases (rs546893082, gnomAD 0.03%). This variant has not been reported in the literature in individuals affected with LOXHD1-related conditions. ClinVar contains an entry for this variant (Variation ID: 179067). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.20

BayesDel_addAF

Benign

-0.30

BayesDel_noAF

Benign

-0.39

CADD

Benign

DANN

Benign

0.94

Eigen

Uncertain

0.34

Eigen_PC

Uncertain

0.37

FATHMM_MKL

Uncertain

0.88

LIST_S2

Uncertain

0.93

D;D;D

M_CAP

Benign

0.037

MetaRNN

Benign

0.31

T;T;T

MetaSVM

Benign

-0.71

MutationTaster

Benign

0.94

N;N;N

PrimateAI

Benign

0.36

PROVEAN

Benign

-1.6

N;.;.

REVEL

Benign

0.25

Sift

Benign

0.33

T;.;.

Sift4G

Benign

0.30

T;.;T

Polyphen

0.96

D;.;.

Vest4

0.33

MutPred

0.67

Loss of MoRF binding (P = 0.0294);Loss of MoRF binding (P = 0.0294);Loss of MoRF binding (P = 0.0294);

MVP

0.21

ClinPred

0.094

GERP RS

5.7

Varity_R

0.075

gMVP

0.60

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.060

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