rs144935513

chr18-46538161-C-Achr18-46538161-C-Gchr18-46538161-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001384474.1(LOXHD1):c.4090G>T(p.Val1364Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000163 in 1,531,776 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00011 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000065 ( 0 hom. )

Consequence

LOXHD1
NM_001384474.1 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:2

Conservation

PhyloP100: 1.03

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 Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.057889193).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LOXHD1	NM_001384474.1 linkuse as main transcript	c.4090G>T	p.Val1364Leu	missense_variant	26/41	ENST00000642948.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LOXHD1	ENST00000642948.1 linkuse as main transcript	c.4090G>T	p.Val1364Leu	missense_variant	26/41		NM_001384474.1	P1

Frequencies

GnomAD3 genomes

AF:

0.000105

AC:

AN:

152222

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000386

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000257

AC:

AN:

155838

Hom.:

AF XY:

0.0000122

AC XY:

AN XY:

82092

show subpopulations

Gnomad AFR exome

AF:

0.000460

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000652

AC:

AN:

1379436

Hom.:

Cov.:

AF XY:

0.00000888

AC XY:

AN XY:

675526

show subpopulations

Gnomad4 AFR exome

AF:

0.000192

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.41e-7

Gnomad4 OTH exome

AF:

0.0000351

GnomAD4 genome

AF:

0.000105

AC:

AN:

152340

Hom.:

Cov.:

AF XY:

0.000121

AC XY:

AN XY:

74482

show subpopulations

Gnomad4 AFR

AF:

0.000385

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000330

Hom.:

Bravo

AF:

0.0000907

ExAC

AF:

0.0000385

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

May 13, 2013

Variant classified as Uncertain Significance - Favor Benign. The Val1364Leu vari ant in LOXHD1 has not been reported in individuals with hearing loss, but has be en identified in 2/178 (1%) Japanese chromosomes by the 1000 Genomes Project (db SNP rs144935513). Although this variant has been seen in the general population, the sample size is not large enough to rule out a pathogenic role. Computationa l analyses (biochemical amino acid properties, conservation, AlignGVGD, and SIFT ) suggest that the variant may not impact the protein, though this information i s not predictive enough to rule out pathogenicity. In summary, the clinical sign ificance of this variant cannot be determined with certainty; however, based upo n its presence in the general population and the computational data, we lean tow ards a more likely benign role. -

Autosomal recessive nonsyndromic hearing loss 77

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Natera, Inc.

Oct 28, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Benign

-0.38

BayesDel_noAF

Benign

-0.47

Cadd

Benign

9.1

Dann

Benign

0.96

Eigen

Benign

-0.41

Eigen_PC

Benign

-0.41

FATHMM_MKL

Benign

0.55

LIST_S2

Uncertain

0.91

D;D;D;D;D;D

M_CAP

Benign

0.023

MetaRNN

Benign

0.058

T;T;T;T;T;T

MetaSVM

Benign

-0.99

MutationTaster

Benign

0.97

D;D;D;D;D;D;N

PrimateAI

Benign

0.29

Sift4G

Benign

0.26

T;T;T;D;.;T

Polyphen

0.87

.;.;.;P;.;.

Vest4

0.27

MutPred

0.49

.;.;.;Loss of loop (P = 0.0804);Loss of loop (P = 0.0804);.;

MVP

0.13

ClinPred

0.12

GERP RS

1.3

Varity_R

0.037

gMVP

0.64

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