rs34589386

Positions:

• chr18-46577801-C-A

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.1876G>T​(p.Gly626Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0141 in 1,551,672 control chromosomes in the GnomAD database, including 267 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 0.015 (22 hom., cov: 32)
  • Exomes 𝑓: 0.014 (245 hom.)
• Consequence: LOXHD1 NM_001384474.1 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:7
• Conservation: PhyloP100: 7.84

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=0.008455843).
• BP6: Variant 18-46577801-C-A is Benign according to our data. Variant chr18-46577801-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 47922.We mark this variant Likely_benign, oryginal submissions are: {Benign=6, Uncertain_significance=1}. Variant chr18-46577801-C-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0154 (2338/152258) while in subpopulation SAS AF= 0.0291 (140/4816). AF 95% confidence interval is 0.0251. There are 22 homozygotes in gnomad4. There are 1112 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 22 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LOXHD1	NM_001384474.1	c.1876G>T	p.Gly626Cys	missense_variant	14/41	ENST00000642948.1	NP_001371403.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LOXHD1	ENST00000642948.1	c.1876G>T	p.Gly626Cys	missense_variant	14/41		NM_001384474.1	ENSP00000496347	P1
LOXHD1	ENST00000536736.5	c.1876G>T	p.Gly626Cys	missense_variant	14/40	5		ENSP00000444586
LOXHD1	ENST00000441551.6	c.1876G>T	p.Gly626Cys	missense_variant	14/39	5		ENSP00000387621
LOXHD1	ENST00000335730.6	n.1189G>T		non_coding_transcript_exon_variant	7/27	2

Frequencies

GnomAD3 genomes AF: 0.0153 AC: 2334 AN: 152140 Hom.: 23 Cov.: 32

Gnomad AFR AF: 0.0178

Gnomad AMI AF: 0.0186

Gnomad AMR AF: 0.0148

Gnomad ASJ AF: 0.0475

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0293

Gnomad FIN AF: 0.00500

Gnomad MID AF: 0.0380

Gnomad NFE AF: 0.0139

Gnomad OTH AF: 0.0162

GnomAD3 exomes AF: 0.0164 AC: 2598 AN: 158178 Hom.: 42 AF XY: 0.0179 AC XY: 1488 AN XY: 83330

Gnomad AFR exome AF: 0.0191

Gnomad AMR exome AF: 0.0119

Gnomad ASJ exome AF: 0.0456

Gnomad EAS exome AF: 0.000265

Gnomad SAS exome AF: 0.0352

Gnomad FIN exome AF: 0.00302

Gnomad NFE exome AF: 0.0134

Gnomad OTH exome AF: 0.0186

GnomAD4 exome AF: 0.0139 AC: 19483 AN: 1399414 Hom.: 245 Cov.: 31 AF XY: 0.0147 AC XY: 10150 AN XY: 690216

Gnomad4 AFR exome AF: 0.0195

Gnomad4 AMR exome AF: 0.0124

Gnomad4 ASJ exome AF: 0.0429

Gnomad4 EAS exome AF: 0.000168

Gnomad4 SAS exome AF: 0.0350

Gnomad4 FIN exome AF: 0.00418

Gnomad4 NFE exome AF: 0.0121

Gnomad4 OTH exome AF: 0.0183

GnomAD4 genome AF: 0.0154 AC: 2338 AN: 152258 Hom.: 22 Cov.: 32 AF XY: 0.0149 AC XY: 1112 AN XY: 74442

Gnomad4 AFR AF: 0.0179

Gnomad4 AMR AF: 0.0148

Gnomad4 ASJ AF: 0.0475

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0291

Gnomad4 FIN AF: 0.00500

Gnomad4 NFE AF: 0.0139

Gnomad4 OTH AF: 0.0165

Alfa AF: 0.0149 Hom.: 36

Bravo AF: 0.0157

TwinsUK AF: 0.0111 AC: 41

ALSPAC AF: 0.0138 AC: 53

ESP6500AA AF: 0.0152 AC: 21

ESP6500EA AF: 0.0141 AC: 45

ExAC AF: 0.0219 AC: 578

Asia WGS AF: 0.0130 AC: 44 AN: 3478

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:3

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	May 18, 2021	- -
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. -
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 06, 2023	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 28, 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. -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 07, 2012	Gly626Cys in Exon 14 of LOXHD1: This variant is not expected to have clinical si gnificance because it has been identified in 1.3% (33/2532) of European American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http ://evs.gs.washington.edu/EVS; dbSNP rs34589386). -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Aug 31, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.54
BayesDel_addAF	Benign	-0.082	T
BayesDel_noAF	Pathogenic	0.14
CADD	Uncertain	25
DANN	Uncertain	0.98
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.89	D;D;D
MetaRNN	Benign	0.0085	T;T;T
MetaSVM	Uncertain	-0.060	T
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.67	T
PROVEAN	Pathogenic	-6.6	D;.;.
REVEL	Uncertain	0.64
Sift	Uncertain	0.0050	D;.;.
Sift4G	Uncertain	0.0020	D;.;D
Polyphen		1.0	D;.;.
Vest4		0.72
ClinPred		0.025	T
GERP RS		5.7
Varity_R		0.26
gMVP		0.72

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: rs34589386; hg19: chr18-44157764;