rs186138859

Positions:

• chr18-46593718-T-C

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.1313A>G​(p.Lys438Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000126 in 1,552,188 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/17 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 0.00032 (2 hom., cov: 32)
  • Exomes 𝑓: 0.00010 (1 hom.)
• Consequence: LOXHD1 NM_001384474.1 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4
• Conservation: PhyloP100: 3.22

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0071510673).
• BP6: Variant 18-46593718-T-C is Benign according to our data. Variant chr18-46593718-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 517560.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1, Benign=2}.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000322 (49/152304) while in subpopulation EAS AF= 0.00753 (39/5178). AF 95% confidence interval is 0.00566. There are 2 homozygotes in gnomad4. There are 26 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LOXHD1	NM_001384474.1	c.1313A>G	p.Lys438Arg	missense_variant	10/41	ENST00000642948.1	NP_001371403.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LOXHD1	ENST00000642948.1	c.1313A>G	p.Lys438Arg	missense_variant	10/41		NM_001384474.1	ENSP00000496347.1
LOXHD1	ENST00000536736.5	c.1313A>G	p.Lys438Arg	missense_variant	10/40	5		ENSP00000444586.1
LOXHD1	ENST00000441551.6	c.1313A>G	p.Lys438Arg	missense_variant	10/39	5		ENSP00000387621.2
LOXHD1	ENST00000335730.6	n.626A>G		non_coding_transcript_exon_variant	3/27	2

Frequencies

GnomAD3 genomes AF: 0.000329 AC: 50 AN: 152186 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00771

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000592 AC: 95 AN: 160374 Hom.: 2 AF XY: 0.000464 AC XY: 39 AN XY: 84052

Gnomad AFR exome AF: 0.000110

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00830

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000104 AC: 146 AN: 1399884 Hom.: 1 Cov.: 31 AF XY: 0.0000941 AC XY: 65 AN XY: 690420

Gnomad4 AFR exome AF: 0.0000949

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00347

Gnomad4 SAS exome AF: 0.0000252

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.000275

GnomAD4 genome AF: 0.000322 AC: 49 AN: 152304 Hom.: 2 Cov.: 32 AF XY: 0.000349 AC XY: 26 AN XY: 74470

Gnomad4 AFR AF: 0.000168

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00753

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00

Bravo AF: 0.000257

ExAC AF: 0.000340 AC: 9

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

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

Likely benign, no assertion criteria provided	clinical testing	Natera, Inc.	Dec 13, 2019	- -
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. -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	May 14, 2018	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 specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Oct 26, 2017

p.Lys438Arg in exon 10 of LOXHD1: This variant is not expected to have clinical significance because it has been identified in 0.8% (95/11866) of East Asian chr omosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitut e.org; dbSNP rs186138859). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.49
CADD	Uncertain	24
DANN	Uncertain	0.98
Eigen	Benign	-0.034
Eigen_PC	Benign	0.14
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Uncertain	0.94	D;D;D
MetaRNN	Benign	0.0072	T;T;T
MetaSVM	Benign	-1.0	T
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-0.77	N;.;.
REVEL	Benign	0.17
Sift	Benign	0.16	T;.;.
Sift4G	Uncertain	0.010	D;.;T
Polyphen		0.59	P;.;.
Vest4		0.20
MVP		0.16
ClinPred		0.094	T
GERP RS		5.8
Varity_R		0.065
gMVP		0.37

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs186138859; hg19: chr18-44173681; COSMIC: COSV105903516;