rs59128481

Positions:

• chr18-46518116-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001384474.1(LOXHD1):​c.5399+13G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0923 in 1,550,968 control chromosomes in the GnomAD database, including 7,153 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.072 (526 hom., cov: 32)
  • Exomes 𝑓: 0.095 (6627 hom.)
• Consequence: LOXHD1 NM_001384474.1 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -1.53

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 18-46518116-C-T is Benign according to our data. Variant chr18-46518116-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 47944.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0992 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LOXHD1	NM_001384474.1	c.5399+13G>A		intron_variant		ENST00000642948.1	NP_001371403.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LOXHD1	ENST00000642948.1	c.5399+13G>A		intron_variant			NM_001384474.1	ENSP00000496347	P1

Frequencies

GnomAD3 genomes AF: 0.0719 AC: 10928 AN: 152070 Hom.: 525 Cov.: 32

Gnomad AFR AF: 0.0225

Gnomad AMI AF: 0.255

Gnomad AMR AF: 0.0804

Gnomad ASJ AF: 0.0925

Gnomad EAS AF: 0.0581

Gnomad SAS AF: 0.0710

Gnomad FIN AF: 0.0444

Gnomad MID AF: 0.0696

Gnomad NFE AF: 0.101

Gnomad OTH AF: 0.0961

GnomAD3 exomes AF: 0.0771 AC: 12082 AN: 156710 Hom.: 576 AF XY: 0.0795 AC XY: 6568 AN XY: 82654

Gnomad AFR exome AF: 0.0224

Gnomad AMR exome AF: 0.0546

Gnomad ASJ exome AF: 0.0981

Gnomad EAS exome AF: 0.0600

Gnomad SAS exome AF: 0.0778

Gnomad FIN exome AF: 0.0454

Gnomad NFE exome AF: 0.102

Gnomad OTH exome AF: 0.0882

GnomAD4 exome AF: 0.0946 AC: 132292 AN: 1398780 Hom.: 6627 Cov.: 33 AF XY: 0.0944 AC XY: 65155 AN XY: 689902

Gnomad4 AFR exome AF: 0.0176

Gnomad4 AMR exome AF: 0.0563

Gnomad4 ASJ exome AF: 0.0966

Gnomad4 EAS exome AF: 0.0388

Gnomad4 SAS exome AF: 0.0785

Gnomad4 FIN exome AF: 0.0488

Gnomad4 NFE exome AF: 0.103

Gnomad4 OTH exome AF: 0.0916

GnomAD4 genome AF: 0.0718 AC: 10923 AN: 152188 Hom.: 526 Cov.: 32 AF XY: 0.0696 AC XY: 5182 AN XY: 74402

Gnomad4 AFR AF: 0.0224

Gnomad4 AMR AF: 0.0802

Gnomad4 ASJ AF: 0.0925

Gnomad4 EAS AF: 0.0575

Gnomad4 SAS AF: 0.0709

Gnomad4 FIN AF: 0.0444

Gnomad4 NFE AF: 0.101

Gnomad4 OTH AF: 0.0951

Alfa AF: 0.0864 Hom.: 127

Bravo AF: 0.0722

Asia WGS AF: 0.0580 AC: 202 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 13, 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. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

not specified Benign:2

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	5213+13G>A in Intron 33 of LOXHD1: This variant is not expected to have clinical significance because it is not located within the conserved splice consensus se quence and has been identified in 11.4% (288/2532) of European American chromoso mes from a broad population by the NHLBI Exome Sequencing Project (http://evs.gs .washington.edu/EVS; dbSNP rs59128481). -

Autosomal recessive nonsyndromic hearing loss 77 Benign:2

Likely benign, 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 and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 10, 2021	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	1.7
DANN	Benign	0.53

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: rs59128481; hg19: chr18-44098079;