rs10163657

Positions:

chr18-46601264-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The ENST00000441551.6(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 (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt. Synonymous variant affecting the same amino acid position (i.e. V363V) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.059 ( 322 hom., cov: 32)

Exomes 𝑓: 0.077 ( 4401 hom. )

Consequence

LOXHD1
ENST00000441551.6 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 5.14

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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 link	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	UniProt
LOXHD1	ENST00000642948.1 link	c.1087G>A	p.Val363Ile	missense_variant	8/41		NM_001384474.1	ENSP00000496347.1	A0A2R8Y7K4
LOXHD1	ENST00000536736.5 link	c.1087G>A	p.Val363Ile	missense_variant	8/40	5		ENSP00000444586.1	F5GZB4
LOXHD1	ENST00000441551.6 link	c.1087G>A	p.Val363Ile	missense_variant	8/39	5		ENSP00000387621.2	Q8IVV2-1
LOXHD1	ENST00000335730.6 link	n.400G>A		non_coding_transcript_exon_variant	1/27	2

Frequencies

GnomAD3 genomes

AF:

0.0590

AC:

8968

AN:

152116

Hom.:

321

Cov.:

show subpopulations

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

show subpopulations

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.:

AF XY:

0.0764

AC XY:

52715

AN XY:

690200

show subpopulations

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.:

AF XY:

0.0564

AC XY:

4198

AN XY:

74428

show subpopulations

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:

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

LINK: link

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	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). -

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

BayesDel_noAF

Benign

-0.58

CADD

Benign

DANN

Uncertain

0.99

Eigen

Benign

-0.68

Eigen_PC

Benign

-0.37

FATHMM_MKL

Benign

0.091

LIST_S2

Benign

0.55

T;T;T

MetaRNN

Benign

0.0015

T;T;T

MetaSVM

Benign

-1.1

PrimateAI

Uncertain

0.71

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

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over