rs143514947

chr18-46483755-AC-A

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_001384474.1(LOXHD1):c.6183-11del variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.303 in 1,549,790 control chromosomes in the GnomAD database, including 75,903 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.24 (5227 hom., cov: 23)
  • Exomes 𝑓: 0.31 (70676 hom.)
• Consequence: LOXHD1 NM_001384474.1 splice_polypyrimidine_tract, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.360

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 -16 ACMG points.

• BP6: Variant 18-46483755-AC-A is Benign according to our data. Variant chr18-46483755-AC-A is described in ClinVar as [Likely_benign]. Clinvar id is 262524.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.327 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LOXHD1	NM_001384474.1	c.6183-11del		splice_polypyrimidine_tract_variant, intron_variant		ENST00000642948.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LOXHD1	ENST00000642948.1	c.6183-11del		splice_polypyrimidine_tract_variant, intron_variant			NM_001384474.1	P1

Frequencies

GnomAD3 genomes AF: 0.236 AC: 35887 AN: 151880 Hom.: 5228 Cov.: 23

Gnomad AFR AF: 0.0777

Gnomad AMI AF: 0.351

Gnomad AMR AF: 0.257

Gnomad ASJ AF: 0.250

Gnomad EAS AF: 0.0112

Gnomad SAS AF: 0.254

Gnomad FIN AF: 0.306

Gnomad MID AF: 0.247

Gnomad NFE AF: 0.330

Gnomad OTH AF: 0.259

GnomAD3 exomes AF: 0.263 AC: 41144 AN: 156302 Hom.: 6105 AF XY: 0.267 AC XY: 22012 AN XY: 82588

Gnomad AFR exome AF: 0.0685

Gnomad AMR exome AF: 0.251

Gnomad ASJ exome AF: 0.246

Gnomad EAS exome AF: 0.00826

Gnomad SAS exome AF: 0.258

Gnomad FIN exome AF: 0.300

Gnomad NFE exome AF: 0.332

Gnomad OTH exome AF: 0.302

GnomAD4 exome AF: 0.310 AC: 433923 AN: 1397792 Hom.: 70676 Cov.: 0 AF XY: 0.310 AC XY: 213431 AN XY: 689212

Gnomad4 AFR exome AF: 0.0681

Gnomad4 AMR exome AF: 0.258

Gnomad4 ASJ exome AF: 0.250

Gnomad4 EAS exome AF: 0.00915

Gnomad4 SAS exome AF: 0.255

Gnomad4 FIN exome AF: 0.302

Gnomad4 NFE exome AF: 0.337

Gnomad4 OTH exome AF: 0.286

GnomAD4 genome AF: 0.236 AC: 35876 AN: 151998 Hom.: 5227 Cov.: 23 AF XY: 0.234 AC XY: 17393 AN XY: 74276

Gnomad4 AFR AF: 0.0775

Gnomad4 AMR AF: 0.257

Gnomad4 ASJ AF: 0.250

Gnomad4 EAS AF: 0.0112

Gnomad4 SAS AF: 0.252

Gnomad4 FIN AF: 0.306

Gnomad4 NFE AF: 0.330

Gnomad4 OTH AF: 0.256

Alfa AF: 0.185 Hom.: 696

Bravo AF: 0.224

Asia WGS AF: 0.160 AC: 558 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 24, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Nonsyndromic Hearing Loss, Recessive Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Autosomal recessive nonsyndromic hearing loss 77 Benign:1

Benign, no assertion criteria provided

clinical testing

Natera, Inc.

Sep 27, 2019

- -

Computational scores

Source: dbNSFP v4.3

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: rs143514947; hg19: chr18-44063718;