rs10163657

Positions:

• chr18-46601264-C-T

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.1087G>A​(p.Val363Ile) variant causes a missense change. The variant allele was found at a frequency of 0.075 in 1,551,622 control chromosomes in the GnomAD database, including 4,723 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.059 (322 hom., cov: 32)
  • Exomes 𝑓: 0.077 (4401 hom.)
• Consequence: LOXHD1 NM_001384474.1 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 5.14

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]

LOXHD1 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0015088618).
• BP6: Variant 18-46601264-C-T is Benign according to our data. Variant chr18-46601264-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 47916.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr18-46601264-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0842 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LOXHD1	NM_001384474.1	c.1087G>A	p.Val363Ile	missense_variant	8/41	ENST00000642948.1	NP_001371403.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LOXHD1	ENST00000642948.1	c.1087G>A	p.Val363Ile	missense_variant	8/41		NM_001384474.1	ENSP00000496347.1
LOXHD1	ENST00000536736.5	c.1087G>A	p.Val363Ile	missense_variant	8/40	5		ENSP00000444586.1
LOXHD1	ENST00000441551.6	c.1087G>A	p.Val363Ile	missense_variant	8/39	5		ENSP00000387621.2
LOXHD1	ENST00000335730.6	n.400G>A		non_coding_transcript_exon_variant	1/27	2

Frequencies

GnomAD3 genomes AF: 0.0590 AC: 8968 AN: 152116 Hom.: 321 Cov.: 32

Gnomad AFR AF: 0.0195

Gnomad AMI AF: 0.137

Gnomad AMR AF: 0.0579

Gnomad ASJ AF: 0.0576

Gnomad EAS AF: 0.0329

Gnomad SAS AF: 0.0444

Gnomad FIN AF: 0.0517

Gnomad MID AF: 0.0665

Gnomad NFE AF: 0.0860

Gnomad OTH AF: 0.0695

GnomAD3 exomes AF: 0.0612 AC: 9685 AN: 158248 Hom.: 349 AF XY: 0.0618 AC XY: 5151 AN XY: 83384

Gnomad AFR exome AF: 0.0189

Gnomad AMR exome AF: 0.0393

Gnomad ASJ exome AF: 0.0625

Gnomad EAS exome AF: 0.0326

Gnomad SAS exome AF: 0.0513

Gnomad FIN exome AF: 0.0521

Gnomad NFE exome AF: 0.0869

Gnomad OTH exome AF: 0.0695

GnomAD4 exome AF: 0.0767 AC: 107390 AN: 1399388 Hom.: 4401 Cov.: 32 AF XY: 0.0764 AC XY: 52715 AN XY: 690200

Gnomad4 AFR exome AF: 0.0183

Gnomad4 AMR exome AF: 0.0409

Gnomad4 ASJ exome AF: 0.0648

Gnomad4 EAS exome AF: 0.0180

Gnomad4 SAS exome AF: 0.0519

Gnomad4 FIN exome AF: 0.0537

Gnomad4 NFE exome AF: 0.0853

Gnomad4 OTH exome AF: 0.0671

GnomAD4 genome AF: 0.0589 AC: 8968 AN: 152234 Hom.: 322 Cov.: 32 AF XY: 0.0564 AC XY: 4198 AN XY: 74428

Gnomad4 AFR AF: 0.0195

Gnomad4 AMR AF: 0.0578

Gnomad4 ASJ AF: 0.0576

Gnomad4 EAS AF: 0.0330

Gnomad4 SAS AF: 0.0449

Gnomad4 FIN AF: 0.0517

Gnomad4 NFE AF: 0.0860

Gnomad4 OTH AF: 0.0688

Alfa AF: 0.0802 Hom.: 1277

Bravo AF: 0.0566

TwinsUK AF: 0.0820 AC: 304

ALSPAC AF: 0.0859 AC: 331

ESP6500AA AF: 0.0181 AC: 25

ESP6500EA AF: 0.0902 AC: 287

ExAC AF: 0.0565 AC: 1436

Asia WGS AF: 0.0380 AC: 132 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	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 07, 2012	Val363Ile in Exon 08 of LOXHD1: This variant is not expected to have clinical si gnificance because it has been identified in 9.1% (231/2532) of European America n chromosomes from a broad population by the NHLBI Exome Sequencing Project (htt p://evs.gs.washington.edu/EVS; dbSNP rs10163657). -
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. -

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:2

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

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.052
BayesDel_addAF	Benign	-0.61	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	18
DANN	Uncertain	0.99
Eigen	Benign	-0.68
Eigen_PC	Benign	-0.37
FATHMM_MKL	Benign	0.091	N
LIST_S2	Benign	0.55	T;T;T
MetaRNN	Benign	0.0015	T;T;T
MetaSVM	Benign	-1.1	T
PrimateAI	Uncertain	0.71	T
PROVEAN	Benign	0.64	N;.;.
REVEL	Benign	0.087
Sift	Benign	1.0	T;.;.
Sift4G	Benign	1.0	T;.;T
Polyphen		0.0	B;.;.
Vest4		0.23
ClinPred		0.019	T
GERP RS		5.6
Varity_R		0.086
gMVP		0.14

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: rs10163657; hg19: chr18-44181227; COSMIC: COSV59665656;