rs189873733

chr18-46477553-G-A

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4 BP6 BS1

The NM_001384474.1(LOXHD1):c.6741C>T(p.Ala2247=) variant causes a synonymous change. The variant allele was found at a frequency of 0.00381 in 1,551,616 control chromosomes in the GnomAD database, including 18 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 0.0031 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0039 (18 hom.)
• Consequence: LOXHD1 NM_001384474.1 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:5
• Conservation: PhyloP100: 4.05

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 Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.17).
• BP6: Variant 18-46477553-G-A is Benign according to our data. Variant chr18-46477553-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 178390.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=1, Benign=2}. Variant chr18-46477553-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00305 (465/152346) while in subpopulation NFE AF= 0.00463 (315/68024). AF 95% confidence interval is 0.00421. There are 0 homozygotes in gnomad4. There are 215 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LOXHD1	NM_001384474.1	c.6741C>T	p.Ala2247=	synonymous_variant	41/41	ENST00000642948.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LOXHD1	ENST00000642948.1	c.6741C>T	p.Ala2247=	synonymous_variant	41/41		NM_001384474.1	P1

Frequencies

GnomAD3 genomes AF: 0.00306 AC: 466 AN: 152228 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00111

Gnomad AMI AF: 0.00329

Gnomad AMR AF: 0.00412

Gnomad ASJ AF: 0.00346

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.00122

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00463

Gnomad OTH AF: 0.00334

GnomAD3 exomes AF: 0.00286 AC: 441 AN: 154122 Hom.: 0 AF XY: 0.00291 AC XY: 238 AN XY: 81872

Gnomad AFR exome AF: 0.00153

Gnomad AMR exome AF: 0.00215

Gnomad ASJ exome AF: 0.00377

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00119

Gnomad FIN exome AF: 0.00162

Gnomad NFE exome AF: 0.00453

Gnomad OTH exome AF: 0.00508

GnomAD4 exome AF: 0.00389 AC: 5447 AN: 1399270 Hom.: 18 Cov.: 31 AF XY: 0.00380 AC XY: 2621 AN XY: 690140

Gnomad4 AFR exome AF: 0.00111

Gnomad4 AMR exome AF: 0.00266

Gnomad4 ASJ exome AF: 0.00373

Gnomad4 EAS exome AF: 0.0000280

Gnomad4 SAS exome AF: 0.00120

Gnomad4 FIN exome AF: 0.00205

Gnomad4 NFE exome AF: 0.00447

Gnomad4 OTH exome AF: 0.00307

GnomAD4 genome AF: 0.00305 AC: 465 AN: 152346 Hom.: 0 Cov.: 33 AF XY: 0.00289 AC XY: 215 AN XY: 74508

Gnomad4 AFR AF: 0.00111

Gnomad4 AMR AF: 0.00411

Gnomad4 ASJ AF: 0.00346

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00124

Gnomad4 FIN AF: 0.00122

Gnomad4 NFE AF: 0.00463

Gnomad4 OTH AF: 0.00331

Alfa AF: 0.00395 Hom.: 1

Bravo AF: 0.00290

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jun 13, 2017	p.Ala2185Ala in Exon 40 of LOXHD1: This variant is not expected to have clinical significance because it does not alter an amino acid residue, is not located wi thin the splice consensus sequence, and has been identified in 0.5% (326/72006) European chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.b roadinstitute.org/; dbSNP rs189873733). -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 12, 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. -
Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 02, 2015	- -

Autosomal recessive nonsyndromic hearing loss 77 Uncertain:2

Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Nov 11, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2023	LOXHD1: BP4 -
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	-0.17
Cadd	Benign	7.3
Dann	Benign	0.75

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: rs189873733; hg19: chr18-44057516;