rs2086005

Positions:

• chr18-46569511-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001384474.1(LOXHD1):​c.2175C>T​(p.Asn725=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.123 in 1,551,864 control chromosomes in the GnomAD database, including 13,200 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.091 (899 hom., cov: 33)
  • Exomes 𝑓: 0.13 (12301 hom.)
• Consequence: LOXHD1 NM_001384474.1 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.452

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.5).
• BP6: Variant 18-46569511-G-A is Benign according to our data. Variant chr18-46569511-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 47926.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr18-46569511-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.452 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.138 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LOXHD1	NM_001384474.1	c.2175C>T	p.Asn725=	synonymous_variant	16/41	ENST00000642948.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LOXHD1	ENST00000642948.1	c.2175C>T	p.Asn725=	synonymous_variant	16/41		NM_001384474.1	P1
LOXHD1	ENST00000536736.5	c.2175C>T	p.Asn725=	synonymous_variant	16/40	5
LOXHD1	ENST00000441551.6	c.2175C>T	p.Asn725=	synonymous_variant	16/39	5
LOXHD1	ENST00000335730.6	n.1488C>T		non_coding_transcript_exon_variant	9/27	2

Frequencies

GnomAD3 genomes AF: 0.0916 AC: 13938 AN: 152194 Hom.: 898 Cov.: 33

Gnomad AFR AF: 0.0262

Gnomad AMI AF: 0.235

Gnomad AMR AF: 0.104

Gnomad ASJ AF: 0.0901

Gnomad EAS AF: 0.0416

Gnomad SAS AF: 0.0528

Gnomad FIN AF: 0.0452

Gnomad MID AF: 0.0918

Gnomad NFE AF: 0.140

Gnomad OTH AF: 0.112

GnomAD3 exomes AF: 0.0942 AC: 15082 AN: 160144 Hom.: 862 AF XY: 0.0947 AC XY: 7953 AN XY: 84012

Gnomad AFR exome AF: 0.0228

Gnomad AMR exome AF: 0.0759

Gnomad ASJ exome AF: 0.101

Gnomad EAS exome AF: 0.0441

Gnomad SAS exome AF: 0.0591

Gnomad FIN exome AF: 0.0528

Gnomad NFE exome AF: 0.143

Gnomad OTH exome AF: 0.115

GnomAD4 exome AF: 0.127 AC: 177356 AN: 1399552 Hom.: 12301 Cov.: 32 AF XY: 0.125 AC XY: 86361 AN XY: 690282

Gnomad4 AFR exome AF: 0.0229

Gnomad4 AMR exome AF: 0.0784

Gnomad4 ASJ exome AF: 0.0986

Gnomad4 EAS exome AF: 0.0244

Gnomad4 SAS exome AF: 0.0588

Gnomad4 FIN exome AF: 0.0523

Gnomad4 NFE exome AF: 0.145

Gnomad4 OTH exome AF: 0.114

GnomAD4 genome AF: 0.0915 AC: 13935 AN: 152312 Hom.: 899 Cov.: 33 AF XY: 0.0858 AC XY: 6391 AN XY: 74474

Gnomad4 AFR AF: 0.0261

Gnomad4 AMR AF: 0.104

Gnomad4 ASJ AF: 0.0901

Gnomad4 EAS AF: 0.0415

Gnomad4 SAS AF: 0.0530

Gnomad4 FIN AF: 0.0452

Gnomad4 NFE AF: 0.140

Gnomad4 OTH AF: 0.111

Alfa AF: 0.120 Hom.: 921

Bravo AF: 0.0936

Asia WGS AF: 0.0380 AC: 130 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 09, 2017	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	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 07, 2012	Asn725Asn in Exon 16 of LOXHD1: This variant is not expected to have clinical s ignificance because it does not alter an amino acid residue, is not located with in the splice consensus sequence, and has been identified in 16.2% (411/2532) of European American chromosomes from a broad population by the NHLBI Exome Sequen cing Project (http://evs.gs.washington.edu/EVS; dbSNP rs2086005). -

Autosomal recessive nonsyndromic hearing loss 77 Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 10, 2021	- -

not provided Benign:2

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

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.50
CADD	Benign	6.7
DANN	Benign	0.68

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: rs2086005; hg19: chr18-44149474; COSMIC: COSV59670255;