18-46546946-T-C

Variant names:

• chr18-46546946-T-C
• rs1893566
• NM_001384474.1:c.3463A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001384474.1(LOXHD1):​c.3463A>G​(p.Arg1155Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.807 in 1,551,372 control chromosomes in the GnomAD database, including 508,247 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. R1155R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.75 (43171 hom., cov: 32)
  • Exomes 𝑓: 0.81 (465076 hom.)
• Consequence: LOXHD1 NM_001384474.1 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 2.27
• Publications: 38 publications found

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 Gene-Disease associations (from GenCC):

• autosomal recessive nonsyndromic hearing loss 77

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, PanelApp Australia, Labcorp Genetics (formerly Invitae), Ambry Genetics
• nonsyndromic genetic hearing loss

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• hearing loss, autosomal recessive

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• Fuchs' endothelial dystrophy

  Inheritance: AD Classification: LIMITED Submitted by: Illumina

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=9.572991E-7).
• BP6: Variant 18-46546946-T-C is Benign according to our data. Variant chr18-46546946-T-C is described in ClinVar as Benign. ClinVar VariationId is 47934.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.826 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001384474.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LOXHD1	NM_001384474.1	MANE Select	c.3463A>G	p.Arg1155Gly	missense	Exon 22 of 41	NP_001371403.1
	LOXHD1	NM_144612.7		c.3463A>G	p.Arg1155Gly	missense	Exon 22 of 40	NP_653213.6
	LOXHD1	NM_001145472.3		c.130A>G	p.Arg44Gly	missense	Exon 4 of 24	NP_001138944.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LOXHD1	ENST00000642948.1	MANE Select	c.3463A>G	p.Arg1155Gly	missense	Exon 22 of 41	ENSP00000496347.1
	LOXHD1	ENST00000300591.11	TSL:1	c.130A>G	p.Arg44Gly	missense	Exon 4 of 24	ENSP00000300591.6
	LOXHD1	ENST00000579038.6	TSL:1	c.-159A>G		5_prime_UTR	Exon 2 of 22	ENSP00000463285.1

Frequencies

GnomAD3 genomes AF: 0.748 AC: 113731 AN: 151982 Hom.: 43156 Cov.: 32

Gnomad AFR AF: 0.634

Gnomad AMI AF: 0.639

Gnomad AMR AF: 0.693

Gnomad ASJ AF: 0.801

Gnomad EAS AF: 0.656

Gnomad SAS AF: 0.749

Gnomad FIN AF: 0.769

Gnomad MID AF: 0.766

Gnomad NFE AF: 0.832

Gnomad OTH AF: 0.776

GnomAD2 exomes AF: 0.757 AC: 119701 AN: 158160 AF XY: 0.765

Gnomad AFR exome AF: 0.630

Gnomad AMR exome AF: 0.627

Gnomad ASJ exome AF: 0.789

Gnomad EAS exome AF: 0.647

Gnomad FIN exome AF: 0.777

Gnomad NFE exome AF: 0.835

Gnomad OTH exome AF: 0.780

GnomAD4 exome AF: 0.813 AC: 1137881 AN: 1399272 Hom.: 465076 Cov.: 60 AF XY: 0.813 AC XY: 561038 AN XY: 690136

African (AFR) AF: 0.624 AC: 19713 AN: 31594

American (AMR) AF: 0.640 AC: 22838 AN: 35698

Ashkenazi Jewish (ASJ) AF: 0.796 AC: 20032 AN: 25174

East Asian (EAS) AF: 0.660 AC: 23577 AN: 35736

South Asian (SAS) AF: 0.759 AC: 60122 AN: 79236

European-Finnish (FIN) AF: 0.773 AC: 38085 AN: 49278

Middle Eastern (MID) AF: 0.768 AC: 4377 AN: 5698

European-Non Finnish (NFE) AF: 0.837 AC: 902779 AN: 1078856

Other (OTH) AF: 0.799 AC: 46358 AN: 58002

GnomAD4 genome AF: 0.748 AC: 113793 AN: 152100 Hom.: 43171 Cov.: 32 AF XY: 0.744 AC XY: 55325 AN XY: 74360

African (AFR) AF: 0.634 AC: 26304 AN: 41482

American (AMR) AF: 0.692 AC: 10580 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.801 AC: 2781 AN: 3472

East Asian (EAS) AF: 0.656 AC: 3380 AN: 5156

South Asian (SAS) AF: 0.748 AC: 3606 AN: 4824

European-Finnish (FIN) AF: 0.769 AC: 8136 AN: 10582

Middle Eastern (MID) AF: 0.765 AC: 225 AN: 294

European-Non Finnish (NFE) AF: 0.832 AC: 56567 AN: 67988

Other (OTH) AF: 0.774 AC: 1631 AN: 2108

Alfa AF: 0.802 Hom.: 160326

Bravo AF: 0.736

TwinsUK AF: 0.832 AC: 3085

ALSPAC AF: 0.833 AC: 3212

ESP6500AA AF: 0.626 AC: 866

ESP6500EA AF: 0.835 AC: 2657

ExAC AF: 0.754 AC: 18823

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

May 07, 2012

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Arg1155Gly in Exon 22 of LOXHD1: This variant is not expected to have clinical s ignificance because it has been identified in 36.2% (254/702) of African America n chromosomes from a broad population by the NHLBI Exome Sequencing Project (htt p://evs.gs.washington.edu/EVS; dbSNP rs1893566).

May 09, 2017

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Autosomal recessive nonsyndromic hearing loss 77 Benign:4

May 28, 2019

Mendelics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Sep 16, 2020

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

Jul 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.047
BayesDel_addAF	Benign	-0.69	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	13
DANN	Benign	0.58
DEOGEN2	Benign	0.0023	T
Eigen	Benign	-0.77
Eigen_PC	Benign	-0.74
FATHMM_MKL	Benign	0.0040	N
LIST_S2	Benign	0.089	T
MetaRNN	Benign	9.6e-7	T
MetaSVM	Benign	-1.0	T
PhyloP100		2.3
PrimateAI	Benign	0.31	T
PROVEAN	Benign	1.1	N
REVEL	Benign	0.049
Sift	Benign	0.45	T
Sift4G	Benign	0.36	T
Polyphen		0.0060	B
Vest4		0.071
ClinPred		0.0020	T
GERP RS		4.9
Varity_R		0.18
gMVP		0.57
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs1893566; hg19: chr18-44126909; COSMIC: COSV107363740; COSMIC: COSV107363740;