rs36086089

Positions:

• chr18-46563190-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001384474.1(LOXHD1):​c.2473G>A​(p.Val825Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0852 in 1,522,664 control chromosomes in the GnomAD database, including 6,175 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.095 (803 hom., cov: 32)
  • Exomes 𝑓: 0.084 (5372 hom.)
• Consequence: LOXHD1 NM_001384474.1 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 0.775

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0016309619).
• BP6: Variant 18-46563190-C-T is Benign according to our data. Variant chr18-46563190-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 47928.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr18-46563190-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.133 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LOXHD1	NM_001384474.1	c.2473G>A	p.Val825Met	missense_variant	18/41	ENST00000642948.1	NP_001371403.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LOXHD1	ENST00000642948.1	c.2473G>A	p.Val825Met	missense_variant	18/41		NM_001384474.1	ENSP00000496347.1
LOXHD1	ENST00000536736.5	c.2473G>A	p.Val825Met	missense_variant	18/40	5		ENSP00000444586.1
LOXHD1	ENST00000441551.6	c.2473G>A	p.Val825Met	missense_variant	18/39	5		ENSP00000387621.2
LOXHD1	ENST00000335730.6	n.1786G>A		non_coding_transcript_exon_variant	11/27	2

Frequencies

GnomAD3 genomes AF: 0.0947 AC: 14394 AN: 152064 Hom.: 800 Cov.: 32

Gnomad AFR AF: 0.136

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0662

Gnomad ASJ AF: 0.118

Gnomad EAS AF: 0.00308

Gnomad SAS AF: 0.125

Gnomad FIN AF: 0.106

Gnomad MID AF: 0.142

Gnomad NFE AF: 0.0788

Gnomad OTH AF: 0.0952

GnomAD3 exomes AF: 0.0867 AC: 13685 AN: 157836 Hom.: 727 AF XY: 0.0918 AC XY: 7633 AN XY: 83168

Gnomad AFR exome AF: 0.138

Gnomad AMR exome AF: 0.0516

Gnomad ASJ exome AF: 0.122

Gnomad EAS exome AF: 0.00319

Gnomad SAS exome AF: 0.143

Gnomad FIN exome AF: 0.0949

Gnomad NFE exome AF: 0.0802

Gnomad OTH exome AF: 0.0952

GnomAD4 exome AF: 0.0841 AC: 115253 AN: 1370480 Hom.: 5372 Cov.: 31 AF XY: 0.0860 AC XY: 57601 AN XY: 670068

Gnomad4 AFR exome AF: 0.138

Gnomad4 AMR exome AF: 0.0530

Gnomad4 ASJ exome AF: 0.119

Gnomad4 EAS exome AF: 0.00200

Gnomad4 SAS exome AF: 0.141

Gnomad4 FIN exome AF: 0.0954

Gnomad4 NFE exome AF: 0.0799

Gnomad4 OTH exome AF: 0.0923

GnomAD4 genome AF: 0.0947 AC: 14413 AN: 152184 Hom.: 803 Cov.: 32 AF XY: 0.0947 AC XY: 7043 AN XY: 74398

Gnomad4 AFR AF: 0.136

Gnomad4 AMR AF: 0.0661

Gnomad4 ASJ AF: 0.118

Gnomad4 EAS AF: 0.00308

Gnomad4 SAS AF: 0.125

Gnomad4 FIN AF: 0.106

Gnomad4 NFE AF: 0.0788

Gnomad4 OTH AF: 0.0938

Alfa AF: 0.0833 Hom.: 813

Bravo AF: 0.0933

TwinsUK AF: 0.0704 AC: 261

ALSPAC AF: 0.0778 AC: 300

ESP6500AA AF: 0.140 AC: 194

ESP6500EA AF: 0.0867 AC: 276

ExAC AF: 0.101 AC: 2588

Asia WGS AF: 0.0780 AC: 272 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 03, 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	Val825Met in Exon 18 of LOXHD1: This variant is not expected to have clinical si gnificance because it has been identified in 14.1% (99/702) of African American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http: //evs.gs.washington.edu/EVS; dbSNP rs36086089). -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 30, 2021	- -

Autosomal recessive nonsyndromic hearing loss 77 Benign:3

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 10, 2021	- -
Benign, 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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:2

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	19
DANN	Benign	0.97
Eigen	Benign	-0.28
Eigen_PC	Benign	-0.19
FATHMM_MKL	Benign	0.44	N
LIST_S2	Benign	0.81	T;T;D
MetaRNN	Benign	0.0016	T;T;T
MetaSVM	Benign	-1.0	T
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-1.7	N;.;.
REVEL	Benign	0.048
Sift	Benign	0.070	T;.;.
Sift4G	Benign	0.17	T;.;T
Polyphen		0.19	B;.;.
Vest4		0.099
ClinPred		0.0056	T
GERP RS		4.0
Varity_R		0.042
gMVP		0.34

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

Other links and lift over

dbSNP: rs36086089; hg19: chr18-44143153;