rs201366522

Positions:

• chr18-46505863-C-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Moderate BP6 BP7 BS2

The NM_001384474.1(LOXHD1):​c.5853G>A​(p.Lys1951=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000565 in 1,551,706 control chromosomes in the GnomAD database, including 3 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 0.00068 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00055 (3 hom.)
• Consequence: LOXHD1 NM_001384474.1 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:6
• Conservation: PhyloP100: 1.41

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 -8 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.28).
• BP6: Variant 18-46505863-C-T is Benign according to our data. Variant chr18-46505863-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 47947.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Uncertain_significance=1, Benign=1}. Variant chr18-46505863-C-T is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=1.41 with no splicing effect.
• BS2: High Homozygotes in GnomAdExome4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LOXHD1	NM_001384474.1	c.5853G>A	p.Lys1951=	synonymous_variant	37/41	ENST00000642948.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LOXHD1	ENST00000642948.1	c.5853G>A	p.Lys1951=	synonymous_variant	37/41		NM_001384474.1	P1

Frequencies

GnomAD3 genomes AF: 0.000677 AC: 103 AN: 152144 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000916

Gnomad ASJ AF: 0.00923

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000750

Gnomad OTH AF: 0.000956

GnomAD3 exomes AF: 0.00103 AC: 162 AN: 156592 Hom.: 0 AF XY: 0.00107 AC XY: 89 AN XY: 82960

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000445

Gnomad ASJ exome AF: 0.0106

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000878

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000859

Gnomad OTH exome AF: 0.00159

GnomAD4 exome AF: 0.000553 AC: 774 AN: 1399444 Hom.: 3 Cov.: 31 AF XY: 0.000566 AC XY: 391 AN XY: 690216

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000616

Gnomad4 ASJ exome AF: 0.00878

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000631

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000412

Gnomad4 OTH exome AF: 0.00124

GnomAD4 genome AF: 0.000676 AC: 103 AN: 152262 Hom.: 0 Cov.: 32 AF XY: 0.000551 AC XY: 41 AN XY: 74438

Gnomad4 AFR AF: 0.0000722

Gnomad4 AMR AF: 0.000915

Gnomad4 ASJ AF: 0.00923

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000750

Gnomad4 OTH AF: 0.000946

Alfa AF: 0.00120 Hom.: 0

Bravo AF: 0.000824

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:6

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 30, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 30, 2015	p.Lys1889Lys in exon 36 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 0.2% (21/8750) of European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.bro adinstitute.org; dbSNP s201366522). -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 24, 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. -

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

Likely benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2022	LOXHD1: BP4, BP7 -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.28
CADD	Benign	10
DANN	Benign	0.69

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: rs201366522; hg19: chr18-44085826;