rs12606417

Positions:

• chr18-46524474-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001384474.1(LOXHD1):​c.4868A>G​(p.Glu1623Gly) variant causes a missense change. The variant allele was found at a frequency of 0.0916 in 1,551,170 control chromosomes in the GnomAD database, including 7,016 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.071 (516 hom., cov: 33)
  • Exomes 𝑓: 0.094 (6500 hom.)
• Consequence: LOXHD1 NM_001384474.1 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 4.34

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0017565191).
• BP6: Variant 18-46524474-T-C is Benign according to our data. Variant chr18-46524474-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 47941.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0983 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LOXHD1	NM_001384474.1	c.4868A>G	p.Glu1623Gly	missense_variant	31/41	ENST00000642948.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LOXHD1	ENST00000642948.1	c.4868A>G	p.Glu1623Gly	missense_variant	31/41		NM_001384474.1	P1

Frequencies

GnomAD3 genomes AF: 0.0712 AC: 10835 AN: 152190 Hom.: 516 Cov.: 33

Gnomad AFR AF: 0.0227

Gnomad AMI AF: 0.253

Gnomad AMR AF: 0.0764

Gnomad ASJ AF: 0.0934

Gnomad EAS AF: 0.0594

Gnomad SAS AF: 0.0738

Gnomad FIN AF: 0.0444

Gnomad MID AF: 0.0728

Gnomad NFE AF: 0.100

Gnomad OTH AF: 0.0937

GnomAD3 exomes AF: 0.0767 AC: 12120 AN: 158082 Hom.: 561 AF XY: 0.0792 AC XY: 6592 AN XY: 83258

Gnomad AFR exome AF: 0.0233

Gnomad AMR exome AF: 0.0530

Gnomad ASJ exome AF: 0.0969

Gnomad EAS exome AF: 0.0615

Gnomad SAS exome AF: 0.0787

Gnomad FIN exome AF: 0.0452

Gnomad NFE exome AF: 0.101

Gnomad OTH exome AF: 0.0900

GnomAD4 exome AF: 0.0938 AC: 131206 AN: 1398862 Hom.: 6500 Cov.: 32 AF XY: 0.0938 AC XY: 64676 AN XY: 689818

Gnomad4 AFR exome AF: 0.0183

Gnomad4 AMR exome AF: 0.0551

Gnomad4 ASJ exome AF: 0.0955

Gnomad4 EAS exome AF: 0.0396

Gnomad4 SAS exome AF: 0.0800

Gnomad4 FIN exome AF: 0.0486

Gnomad4 NFE exome AF: 0.102

Gnomad4 OTH exome AF: 0.0912

GnomAD4 genome AF: 0.0711 AC: 10829 AN: 152308 Hom.: 516 Cov.: 33 AF XY: 0.0690 AC XY: 5140 AN XY: 74476

Gnomad4 AFR AF: 0.0226

Gnomad4 AMR AF: 0.0763

Gnomad4 ASJ AF: 0.0934

Gnomad4 EAS AF: 0.0588

Gnomad4 SAS AF: 0.0734

Gnomad4 FIN AF: 0.0444

Gnomad4 NFE AF: 0.100

Gnomad4 OTH AF: 0.0927

Alfa AF: 0.0965 Hom.: 1617

Bravo AF: 0.0711

TwinsUK AF: 0.103 AC: 381

ALSPAC AF: 0.0986 AC: 380

ESP6500AA AF: 0.0260 AC: 36

ESP6500EA AF: 0.115 AC: 366

ExAC AF: 0.0742 AC: 1881

Asia WGS AF: 0.0590 AC: 204 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

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	Glu1623Gly in Exon 31 of LOXHD1: This variant is not expected to have clinical s ignificance because it has been identified in 11.1% (281/2532) of European Ameri can chromosomes from a broad population by the NHLBI Exome Sequencing Project (h ttp://evs.gs.washington.edu/EVS; dbSNP rs12606417). -

Autosomal recessive nonsyndromic hearing loss 77 Benign:3

Likely benign, 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 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. -
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:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.50
CADD	Uncertain	26
DANN	Uncertain	0.98
Eigen	Benign	-0.0081
Eigen_PC	Benign	0.088
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.87	D;D;D;D;D;D
MetaRNN	Benign	0.0018	T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	0.025	P;P;P;P;P;P;P
PrimateAI	Benign	0.38	T
Sift4G	Uncertain	0.057	T;T;D;D;.;T
Polyphen		0.97	.;.;.;D;.;.
Vest4		0.19
ClinPred		0.034	T
GERP RS		5.1
Varity_R		0.65
gMVP		0.45

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: rs12606417; hg19: chr18-44104437; COSMIC: COSV56061462; COSMIC: COSV56061462;