rs370616818

Positions:

• chr18-46560120-G-A
• chr18-46560120-G-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Moderate BP6 BP7 BS2

The NM_001384474.1(LOXHD1):​c.3024C>T​(p.Val1008=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00162 in 1,270,194 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. V1008V) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0013 (0 hom., cov: 30)
  • Exomes 𝑓: 0.0016 (3 hom.)
• Consequence: LOXHD1 NM_001384474.1 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:7
• Conservation: PhyloP100: -0.774

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]

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.28).
• BP6: Variant 18-46560120-G-A is Benign according to our data. Variant chr18-46560120-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 227515.We mark this variant Likely_benign, oryginal submissions are: {Benign=1, Likely_benign=5, Uncertain_significance=1}. Variant chr18-46560120-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-0.774 with no splicing effect.
• BS2: High Homozygotes in GnomAdExome4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LOXHD1	NM_001384474.1	c.3024C>T	p.Val1008=	synonymous_variant	19/41	ENST00000642948.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LOXHD1	ENST00000642948.1	c.3024C>T	p.Val1008=	synonymous_variant	19/41		NM_001384474.1	P1
LOXHD1	ENST00000536736.5	c.3024C>T	p.Val1008=	synonymous_variant	19/40	5
LOXHD1	ENST00000441551.6	c.2599-2631C>T		intron_variant		5
LOXHD1	ENST00000335730.6	n.2337C>T		non_coding_transcript_exon_variant	12/27	2

Frequencies

GnomAD3 genomes AF: 0.00132 AC: 159 AN: 120512 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.000471

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000576

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000292

Gnomad FIN AF: 0.00326

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00193

Gnomad OTH AF: 0.00120

GnomAD3 exomes AF: 0.000990 AC: 156 AN: 157646 Hom.: 0 AF XY: 0.00113 AC XY: 94 AN XY: 83112

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000364

Gnomad ASJ exome AF: 0.000118

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00131

Gnomad NFE exome AF: 0.00202

Gnomad OTH exome AF: 0.000449

GnomAD4 exome AF: 0.00165 AC: 1894 AN: 1149632 Hom.: 3 Cov.: 38 AF XY: 0.00166 AC XY: 930 AN XY: 561842

Gnomad4 AFR exome AF: 0.000246

Gnomad4 AMR exome AF: 0.000461

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000260

Gnomad4 FIN exome AF: 0.00158

Gnomad4 NFE exome AF: 0.00194

Gnomad4 OTH exome AF: 0.00121

GnomAD4 genome AF: 0.00132 AC: 159 AN: 120562 Hom.: 0 Cov.: 30 AF XY: 0.00138 AC XY: 77 AN XY: 55668

Gnomad4 AFR AF: 0.000470

Gnomad4 AMR AF: 0.000574

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000293

Gnomad4 FIN AF: 0.00326

Gnomad4 NFE AF: 0.00193

Gnomad4 OTH AF: 0.00119

Alfa AF: 0.00152 Hom.: 0

Bravo AF: 0.000990

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:7

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Autosomal recessive nonsyndromic hearing loss 77 Uncertain:1 Benign:2

Uncertain significance, 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, 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. -
Likely benign, no assertion criteria provided	clinical testing	Natera, Inc.	Dec 17, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	Counsyl	Nov 03, 2017	- -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2022	LOXHD1: BP4, BP7 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 22, 2018	- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Aug 18, 2015

p.Val1008Val in exon 19 of LOXHD1: This variant is not expected to have clinical significance because it does not alter an amino acid residue, is not located wi thin the splice consensus sequence, and has been identified in 0.4% (5/1210) of Finnish chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broad institute.org; dbSNP rs370616818). -

LOXHD1-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 20, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.28
CADD	Benign	3.1
DANN	Benign	0.69

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: rs370616818; hg19: chr18-44140083;