rs34723936

Variant names:

• chr18-46566324-G-A
• rs34723936
• NM_001384474.1:c.2370C>T

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The NM_001384474.1(LOXHD1):​c.2370C>T​(p.Asp790Asp) variant causes a synonymous change. The variant allele was found at a frequency of 0.00468 in 1,551,864 control chromosomes in the GnomAD database, including 193 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.017 (72 hom., cov: 33)
  • Exomes 𝑓: 0.0034 (121 hom.)
• Consequence: LOXHD1 NM_001384474.1 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 4.14

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 -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.44).
• BP6: Variant 18-46566324-G-A is Benign according to our data. Variant chr18-46566324-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 178614.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0522 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LOXHD1	NM_001384474.1	c.2370C>T	p.Asp790Asp	synonymous_variant	Exon 17 of 41	ENST00000642948.1	NP_001371403.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LOXHD1	ENST00000642948.1	c.2370C>T	p.Asp790Asp	synonymous_variant	Exon 17 of 41		NM_001384474.1	ENSP00000496347.1
LOXHD1	ENST00000536736.5	c.2370C>T	p.Asp790Asp	synonymous_variant	Exon 17 of 40	5		ENSP00000444586.1
LOXHD1	ENST00000441551.6	c.2370C>T	p.Asp790Asp	synonymous_variant	Exon 17 of 39	5		ENSP00000387621.2
LOXHD1	ENST00000335730.6	n.1683C>T		non_coding_transcript_exon_variant	Exon 10 of 27	2

Frequencies

GnomAD3 genomes AF: 0.0165 AC: 2512 AN: 152208 Hom.: 69 Cov.: 33

Gnomad AFR AF: 0.0541

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00484

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00212

Gnomad SAS AF: 0.0319

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000176

Gnomad OTH AF: 0.00955

GnomAD3 exomes AF: 0.00790 AC: 1257 AN: 159036 Hom.: 37 AF XY: 0.00909 AC XY: 761 AN XY: 83690

Gnomad AFR exome AF: 0.0522

Gnomad AMR exome AF: 0.00222

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00177

Gnomad SAS exome AF: 0.0307

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000212

Gnomad OTH exome AF: 0.00244

GnomAD4 exome AF: 0.00338 AC: 4736 AN: 1399538 Hom.: 121 Cov.: 31 AF XY: 0.00408 AC XY: 2817 AN XY: 690274

Gnomad4 AFR exome AF: 0.0546

Gnomad4 AMR exome AF: 0.00258

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00283

Gnomad4 SAS exome AF: 0.0293

Gnomad4 FIN exome AF: 0.0000203

Gnomad4 NFE exome AF: 0.000154

Gnomad4 OTH exome AF: 0.00537

GnomAD4 genome AF: 0.0166 AC: 2532 AN: 152326 Hom.: 72 Cov.: 33 AF XY: 0.0165 AC XY: 1229 AN XY: 74488

Gnomad4 AFR AF: 0.0541

Gnomad4 AMR AF: 0.00483

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00193

Gnomad4 SAS AF: 0.0321

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000176

Gnomad4 OTH AF: 0.0151

Alfa AF: 0.00670 Hom.: 17

Bravo AF: 0.0175

Asia WGS AF: 0.0370 AC: 128 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Dec 18, 2017

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 07, 2012

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Asp790Asp in Exon 17 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 4.0% (28/702) of Af rican American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS; dbSNP rs34723936). -

Autosomal recessive nonsyndromic hearing loss 77 Benign:3

Nov 29, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 16, 2020

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

not provided Benign:3

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 23, 2018

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.44
CADD	Benign	9.0
DANN	Benign	0.73

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: rs34723936; hg19: chr18-44146287;