rs117297079

chr18-46538252-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BS1 BS2

The NM_001384474.1(LOXHD1):c.3999C>T(p.Cys1333=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00774 in 1,551,238 control chromosomes in the GnomAD database, including 58 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 0.0062 (8 hom., cov: 32)
  • Exomes 𝑓: 0.0079 (50 hom.)
• Consequence: LOXHD1 NM_001384474.1 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:5
• Conservation: PhyloP100: -1.89

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.71).
• BP6: Variant 18-46538252-G-A is Benign according to our data. Variant chr18-46538252-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 47936.We mark this variant Likely_benign, oryginal submissions are: {Benign=2, Likely_benign=2, Uncertain_significance=1}.
• BP7: Synonymous conserved (PhyloP=-1.89 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00624 (950/152280) while in subpopulation NFE AF= 0.00878 (597/68018). AF 95% confidence interval is 0.00819. There are 8 homozygotes in gnomad4. There are 501 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 8 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LOXHD1	NM_001384474.1	c.3999C>T	p.Cys1333=	synonymous_variant	26/41	ENST00000642948.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LOXHD1	ENST00000642948.1	c.3999C>T	p.Cys1333=	synonymous_variant	26/41		NM_001384474.1	P1

Frequencies

GnomAD3 genomes AF: 0.00624 AC: 950 AN: 152162 Hom.: 8 Cov.: 32

Gnomad AFR AF: 0.00140

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00334

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0221

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00878

Gnomad OTH AF: 0.00430

GnomAD3 exomes AF: 0.00604 AC: 948 AN: 156950 Hom.: 12 AF XY: 0.00588 AC XY: 487 AN XY: 82780

Gnomad AFR exome AF: 0.000575

Gnomad AMR exome AF: 0.00214

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000351

Gnomad FIN exome AF: 0.0200

Gnomad NFE exome AF: 0.00887

Gnomad OTH exome AF: 0.00564

GnomAD4 exome AF: 0.00791 AC: 11059 AN: 1398958 Hom.: 50 Cov.: 31 AF XY: 0.00771 AC XY: 5316 AN XY: 689942

Gnomad4 AFR exome AF: 0.000791

Gnomad4 AMR exome AF: 0.00246

Gnomad4 ASJ exome AF: 0.000159

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000417

Gnomad4 FIN exome AF: 0.0222

Gnomad4 NFE exome AF: 0.00874

Gnomad4 OTH exome AF: 0.00652

GnomAD4 genome AF: 0.00624 AC: 950 AN: 152280 Hom.: 8 Cov.: 32 AF XY: 0.00673 AC XY: 501 AN XY: 74452

Gnomad4 AFR AF: 0.00140

Gnomad4 AMR AF: 0.00333

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0221

Gnomad4 NFE AF: 0.00878

Gnomad4 OTH AF: 0.00425

Alfa AF: 0.00697 Hom.: 5

Bravo AF: 0.00480

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Autosomal recessive nonsyndromic hearing loss 77 Uncertain:1 Benign:1

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Dec 10, 2019	- -
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 specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 07, 2012	Cys1333Cys in Exon 26 of LOXHD1: This variant is not expected to have clinical significance because it does not alter an amino acid residue, is not located wit hin the splice consensus sequence, and has been identified in 1.0% (26/2532) of European American chromosomes from a broad population by the NHLBI Exome Sequenc ing Project (http://evs.gs.washington.edu/EVS; dbSNP rs117297079). -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 23, 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. -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	LOXHD1: BP4, BP7, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.71
Cadd	Benign	1.4
Dann	Benign	0.48

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: rs117297079; hg19: chr18-44118215; COSMIC: COSV56061687;