rs367630521

Positions:

• chr18-46560230-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.2914G>A​(p.Glu972Lys) variant causes a missense change. The variant allele was found at a frequency of 0.000228 in 1,551,574 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/16 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 0.0012 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00012 (2 hom.)
• Consequence: LOXHD1 NM_001384474.1 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:3
• Conservation: PhyloP100: 3.90

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=0.007861972).
• BP6: Variant 18-46560230-C-T is Benign according to our data. Variant chr18-46560230-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 228822.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=4}.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00122 (186/152302) while in subpopulation AFR AF= 0.00421 (175/41578). AF 95% confidence interval is 0.0037. There are 0 homozygotes in gnomad4. There are 90 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LOXHD1	NM_001384474.1	c.2914G>A	p.Glu972Lys	missense_variant	19/41	ENST00000642948.1	NP_001371403.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LOXHD1	ENST00000642948.1	c.2914G>A	p.Glu972Lys	missense_variant	19/41		NM_001384474.1	ENSP00000496347	P1
LOXHD1	ENST00000536736.5	c.2914G>A	p.Glu972Lys	missense_variant	19/40	5		ENSP00000444586
LOXHD1	ENST00000441551.6	c.2599-2741G>A		intron_variant		5		ENSP00000387621
LOXHD1	ENST00000335730.6	n.2227G>A		non_coding_transcript_exon_variant	12/27	2

Frequencies

GnomAD3 genomes AF: 0.00122 AC: 185 AN: 152184 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00420

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000458

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.000309 AC: 49 AN: 158796 Hom.: 0 AF XY: 0.000203 AC XY: 17 AN XY: 83566

Gnomad AFR exome AF: 0.00443

Gnomad AMR exome AF: 0.000161

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000265

Gnomad SAS exome AF: 0.0000439

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000443

GnomAD4 exome AF: 0.000119 AC: 167 AN: 1399272 Hom.: 2 Cov.: 37 AF XY: 0.0000942 AC XY: 65 AN XY: 690078

Gnomad4 AFR exome AF: 0.00437

Gnomad4 AMR exome AF: 0.000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000112

Gnomad4 SAS exome AF: 0.0000127

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000278

Gnomad4 OTH exome AF: 0.000224

GnomAD4 genome AF: 0.00122 AC: 186 AN: 152302 Hom.: 0 Cov.: 32 AF XY: 0.00121 AC XY: 90 AN XY: 74460

Gnomad4 AFR AF: 0.00421

Gnomad4 AMR AF: 0.000457

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000194

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.000706 Hom.: 0

Bravo AF: 0.00138

ESP6500AA AF: 0.00289 AC: 4

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000206 AC: 12

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Autosomal recessive nonsyndromic hearing loss 77 Uncertain:3 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 12, 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. -
Uncertain significance, criteria provided, single submitter	research	UNC Molecular Genetics Laboratory, University of North Carolina at Chapel Hill	-	The LOXHD1 c.2914G>A (p.E972K) missense variant has not been reported in association with hearing loss; therefore is a variant of uncertain significance. -
Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Jan 08, 2020	- -

not provided Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 03, 2017	- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jan 03, 2016

Variant classified as Uncertain Significance - Favor Benign. The p.Glu972Lys var iant in LOXHD1 has not been previously reported in individuals with hearing loss , but has been identified in 0.32% (9/2784) of African chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs367630521) . Computational prediction tools and conservation analysis suggest that the p.Gl u972Lys variant may not impact the protein, though this information is not predi ctive enough to rule out pathogenicity. In summary, while the clinical significa nce of the p.Glu972Lys variant is uncertain, these data suggest that it is more likely to be benign. -

LOXHD1-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 17, 2024

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_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	20
DANN	Benign	0.93
Eigen	Benign	0.036
Eigen_PC	Benign	0.064
FATHMM_MKL	Benign	0.58	D
LIST_S2	Benign	0.77	T;T
M_CAP	Benign	0.052	D
MetaRNN	Benign	0.0079	T;T
MetaSVM	Benign	-0.94	T
MutationTaster	Benign	1.0	D;N;N
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-0.54	N;.
REVEL	Benign	0.050
Sift	Benign	0.17	T;.
Sift4G	Benign	0.70	T;.
Polyphen		0.0070	B;.
Vest4		0.40
MVP		0.061
ClinPred		0.0096	T
GERP RS		3.1
gMVP		0.32

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: rs367630521; hg19: chr18-44140193;