rs118174674

chr18-46557437-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001384474.1(LOXHD1):c.3269G>A(p.Arg1090Gln) variant causes a missense change. The variant allele was found at a frequency of 0.0175 in 1,552,130 control chromosomes in the GnomAD database, including 264 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.013 (19 hom., cov: 32)
  • Exomes 𝑓: 0.018 (245 hom.)
• Consequence: LOXHD1 NM_001384474.1 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:7 O:1
• Conservation: PhyloP100: 5.03

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.013051391).
• BP6: Variant 18-46557437-C-T is Benign according to our data. Variant chr18-46557437-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 47933.We mark this variant Likely_benign, oryginal submissions are: {Benign=6, not_provided=1, Uncertain_significance=1}.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0133 (2031/152252) while in subpopulation NFE AF= 0.0219 (1488/68022). AF 95% confidence interval is 0.021. There are 19 homozygotes in gnomad4. There are 910 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 19 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LOXHD1	NM_001384474.1	c.3269G>A	p.Arg1090Gln	missense_variant	21/41	ENST00000642948.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LOXHD1	ENST00000642948.1	c.3269G>A	p.Arg1090Gln	missense_variant	21/41		NM_001384474.1	P1

Frequencies

GnomAD3 genomes AF: 0.0134 AC: 2031 AN: 152134 Hom.: 19 Cov.: 32

Gnomad AFR AF: 0.00304

Gnomad AMI AF: 0.0186

Gnomad AMR AF: 0.0154

Gnomad ASJ AF: 0.0101

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00207

Gnomad FIN AF: 0.00773

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.0219

Gnomad OTH AF: 0.0163

GnomAD3 exomes AF: 0.0122 AC: 1954 AN: 160138 Hom.: 15 AF XY: 0.0118 AC XY: 991 AN XY: 84018

Gnomad AFR exome AF: 0.00224

Gnomad AMR exome AF: 0.00888

Gnomad ASJ exome AF: 0.0104

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00211

Gnomad FIN exome AF: 0.00719

Gnomad NFE exome AF: 0.0224

Gnomad OTH exome AF: 0.0140

GnomAD4 exome AF: 0.0179 AC: 25077 AN: 1399878 Hom.: 245 Cov.: 33 AF XY: 0.0177 AC XY: 12249 AN XY: 690416

Gnomad4 AFR exome AF: 0.00241

Gnomad4 AMR exome AF: 0.0106

Gnomad4 ASJ exome AF: 0.0105

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00273

Gnomad4 FIN exome AF: 0.00818

Gnomad4 NFE exome AF: 0.0211

Gnomad4 OTH exome AF: 0.0149

GnomAD4 genome AF: 0.0133 AC: 2031 AN: 152252 Hom.: 19 Cov.: 32 AF XY: 0.0122 AC XY: 910 AN XY: 74444

Gnomad4 AFR AF: 0.00303

Gnomad4 AMR AF: 0.0154

Gnomad4 ASJ AF: 0.0101

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00208

Gnomad4 FIN AF: 0.00773

Gnomad4 NFE AF: 0.0219

Gnomad4 OTH AF: 0.0161

Alfa AF: 0.0194 Hom.: 42

Bravo AF: 0.0141

TwinsUK AF: 0.0197 AC: 73

ALSPAC AF: 0.0252 AC: 97

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.0192 AC: 61

ExAC AF: 0.00831 AC: 240

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:7 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

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

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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. -
not provided, no classification provided	phenotyping only	GenomeConnect, ClinGen	-	Variant interpretted as Uncertain significance and reported on 07/21/2017 by GTR ID Shodair Children's Hospital. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 01, 2023	- -

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 07, 2012	Arg1090Gln in Exon 21 of LOXHD1: This variant is not expected to have clinical s ignificance because it has been identified in 2.1% (54/2532) of European America n chromosomes from a broad population by the NHLBI Exome Sequencing Project (htt p://evs.gs.washington.edu/EVS; dbSNP rs118174674). -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 29, 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. -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	May 16, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.30
BayesDel_addAF	Benign	-0.035	T
BayesDel_noAF	Pathogenic	0.20
Cadd	Pathogenic	26
Dann	Uncertain	0.99
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.97	D;D;D
MetaRNN	Benign	0.013	T;T;T
MetaSVM	Benign	-0.55	T
MutationTaster	Benign	1.0	D;D;D;D;D;D
PrimateAI	Uncertain	0.52	T
PROVEAN	Uncertain	-2.5	D;.;.
REVEL	Uncertain	0.52
Sift	Uncertain	0.014	D;.;.
Sift4G	Uncertain	0.010	D;.;D
Polyphen		1.0	D;.;.
Vest4		0.60
ClinPred		0.037	T
GERP RS		5.2
Varity_R		0.11
gMVP		0.71

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs118174674; hg19: chr18-44137400;