18-46560281-C-G

Variant names:

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBS1_SupportingBS2

The NM_001384474.1(LOXHD1):c.2863G>C(p.Glu955Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00016 in 1,551,962 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/16 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 0.00012 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00016 ( 3 hom. )

Consequence

LOXHD1
NM_001384474.1 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:5

Conservation

PhyloP100: 1.25

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 -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.025721014).

BS1

Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.000164 (230/1399614) while in subpopulation MID AF= 0.0121 (69/5702). AF 95% confidence interval is 0.00981. There are 3 homozygotes in gnomad4_exome. There are 118 alleles in male gnomad4_exome subpopulation. Median coverage is 37. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High Homozygotes in GnomAdExome4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LOXHD1	NM_001384474.1 link	c.2863G>C	p.Glu955Gln	missense_variant	Exon 19 of 41	ENST00000642948.1	NP_001371403.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
LOXHD1	ENST00000642948.1 link	c.2863G>C	p.Glu955Gln	missense_variant	Exon 19 of 41		NM_001384474.1	ENSP00000496347.1	A0A2R8Y7K4
LOXHD1	ENST00000536736.5 link	c.2863G>C	p.Glu955Gln	missense_variant	Exon 19 of 40	5		ENSP00000444586.1	F5GZB4
LOXHD1	ENST00000441551.6 link	c.2598+2784G>C		intron_variant	Intron 18 of 38	5		ENSP00000387621.2	Q8IVV2-1
LOXHD1	ENST00000335730.6 link	n.2176G>C		non_coding_transcript_exon_variant	Exon 12 of 27	2

Frequencies

GnomAD3 genomes

AF:

0.000131

AC:

AN:

152230

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000482

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000262

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0158

Gnomad NFE

AF:

0.000118

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000291

AC:

AN:

158098

Hom.:

AF XY:

0.000324

AC XY:

AN XY:

83206

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000605

Gnomad ASJ exome

AF:

0.000353

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000527

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000229

Gnomad OTH exome

AF:

0.000444

GnomAD4 exome

AF:

0.000164

AC:

230

AN:

1399614

Hom.:

Cov.:

AF XY:

0.000171

AC XY:

118

AN XY:

690336

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000644

Gnomad4 ASJ exome

AF:

0.000238

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000454

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000751

Gnomad4 OTH exome

AF:

0.000258

GnomAD4 genome

AF:

0.000125

AC:

AN:

152348

Hom.:

Cov.:

AF XY:

0.000121

AC XY:

AN XY:

74490

show subpopulations

Gnomad4 AFR

AF:

0.0000481

Gnomad4 AMR

AF:

0.000261

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000118

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000248

Hom.:

Bravo

AF:

0.000193

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ExAC

AF:

0.000215

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Autosomal recessive nonsyndromic hearing loss 77

Pathogenic:1Uncertain:2

Aug 20, 2024

Laboratory of Prof. Karen Avraham, Tel Aviv University

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

This p.(Glu955Gln) variant is rare and preddicted deleterious by many prediction programs. It was detected in compound heterozygosity with another variant, p.(Arg524His), also rare and predicted deleterious, in a hearing impaired individual with a sloping audiogram, normal-to-severe HL. -

Jan 24, 2020

Natera, Inc.

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

not provided

Uncertain:2

Aug 16, 2016

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

not specified

Uncertain:1

May 05, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant classified as Uncertain Significance - Favor Benign. The p.Glu955Gln var iant in LOXHD1 has not been previously reported in individuals with hearing loss , but it has been identified in 11/21292 of the total chromosomes by the chromos omes by the Exome Aggregation Consortium, which includes several populations (Ex AC, http://exac.broadinstitute.org; dbSNP rs548893604). Although this variant ha s been seen in the general population, its frequency is not high enough to rule out a pathogenic role. Computational prediction tools and conservation analyses suggest that this variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity. Of note, the glutamic acid (Gl u) at amino acid position 955 is not conserved through species, with one mammal (Golden hamster) having a glutamine (Gln) at this position. In summary, while t he clinical significance of this variant is uncertain, these data suggest that i t is more likely to be benign. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.50

BayesDel_noAF

Benign

-0.61

CADD

Benign

DANN

Benign

0.64

Eigen

Benign

-0.021

Eigen_PC

Benign

0.0080

FATHMM_MKL

Uncertain

0.86

LIST_S2

Benign

0.50

T;T

M_CAP

Benign

0.083

MetaRNN

Benign

0.026

T;T

MetaSVM

Benign

-0.88

PrimateAI

Uncertain

0.51

PROVEAN

Benign

-0.71

N;.

REVEL

Benign

0.067

Sift

Benign

0.56

T;.

Sift4G

Uncertain

0.021

D;.

Polyphen

0.84

P;.

Vest4

0.21

MutPred

0.21

Loss of solvent accessibility (P = 0.1868);Loss of solvent accessibility (P = 0.1868);

MVP

0.048

ClinPred

0.041

GERP RS

4.7

gMVP

0.22

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