18-46507526-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.5692+12G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00184 in 1,551,298 control chromosomes in the GnomAD database, including 24 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 0.0015 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0019 (24 hom.)
• Consequence: LOXHD1 NM_001384474.1 intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: -3.09

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 (BayesDel_noAF=-0.81).
• BP6: Variant 18-46507526-C-T is Benign according to our data. Variant chr18-46507526-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 178394.We mark this variant Likely_benign, oryginal submissions are: {Benign=3, Uncertain_significance=1}.
• BS1: Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.00188 (2629/1399002) while in subpopulation MID AF= 0.0302 (172/5694). AF 95% confidence interval is 0.0265. There are 24 homozygotes in gnomad4_exome. There are 1376 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LOXHD1	NM_001384474.1	c.5692+12G>A		intron_variant		ENST00000642948.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LOXHD1	ENST00000642948.1	c.5692+12G>A		intron_variant			NM_001384474.1	P1

Frequencies

GnomAD3 genomes AF: 0.00149 AC: 227 AN: 152178 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000290

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00373

Gnomad ASJ AF: 0.00894

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00332

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0316

Gnomad NFE AF: 0.00132

Gnomad OTH AF: 0.00430

GnomAD3 exomes AF: 0.00329 AC: 513 AN: 156014 Hom.: 4 AF XY: 0.00335 AC XY: 277 AN XY: 82676

Gnomad AFR exome AF: 0.000126

Gnomad AMR exome AF: 0.00490

Gnomad ASJ exome AF: 0.0127

Gnomad EAS exome AF: 0.0000918

Gnomad SAS exome AF: 0.00540

Gnomad FIN exome AF: 0.000119

Gnomad NFE exome AF: 0.00216

Gnomad OTH exome AF: 0.00616

GnomAD4 exome AF: 0.00188 AC: 2629 AN: 1399002 Hom.: 24 Cov.: 31 AF XY: 0.00199 AC XY: 1376 AN XY: 690002

Gnomad4 AFR exome AF: 0.00120

Gnomad4 AMR exome AF: 0.00541

Gnomad4 ASJ exome AF: 0.0109

Gnomad4 EAS exome AF: 0.0000280

Gnomad4 SAS exome AF: 0.00567

Gnomad4 FIN exome AF: 0.0000203

Gnomad4 NFE exome AF: 0.00118

Gnomad4 OTH exome AF: 0.00386

GnomAD4 genome AF: 0.00148 AC: 226 AN: 152296 Hom.: 0 Cov.: 33 AF XY: 0.00154 AC XY: 115 AN XY: 74472

Gnomad4 AFR AF: 0.000289

Gnomad4 AMR AF: 0.00373

Gnomad4 ASJ AF: 0.00894

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00332

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00132

Gnomad4 OTH AF: 0.00426

Alfa AF: 0.00245 Hom.: 0

Bravo AF: 0.00214

Asia WGS AF: 0.00462 AC: 16 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jun 16, 2015	5506+12G>A in Intron 35 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 0.6% (48/7914) of South Asian chromosomes incl uding 1 homozygote, and in 0.6% (50/3710) of European chromosomes by the Exome A ggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs200518261). -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Autosomal recessive nonsyndromic hearing loss 77 Uncertain:1

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:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
Cadd	Benign	0.037
Dann	Benign	0.63

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: rs200518261; hg19: chr18-44087489;