chr18-46518141-T-C

Position:

chr18-46518141-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001384474.1(LOXHD1):c.5387A>G(p.Lys1796Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000247 in 1,551,528 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts 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: 0.00026 ( 1 hom. )

Consequence

LOXHD1
NM_001384474.1 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:6

Conservation

PhyloP100: 7.63

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 Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.2411823).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LOXHD1	NM_001384474.1 linkuse as main transcript	c.5387A>G	p.Lys1796Arg	missense_variant	34/41	ENST00000642948.1	NP_001371403.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LOXHD1	ENST00000642948.1 linkuse as main transcript	c.5387A>G	p.Lys1796Arg	missense_variant	34/41		NM_001384474.1	ENSP00000496347	P1

Frequencies

GnomAD3 genomes

AF:

0.000105

AC:

AN:

152150

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

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:

0.000221

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000886

AC:

AN:

157936

Hom.:

AF XY:

0.0000841

AC XY:

AN XY:

83240

show subpopulations

Gnomad AFR exome

AF:

0.000230

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:

0.000197

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000263

AC:

368

AN:

1399378

Hom.:

Cov.:

AF XY:

0.000255

AC XY:

176

AN XY:

690192

show subpopulations

Gnomad4 AFR exome

AF:

0.0000316

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:

0.0000609

Gnomad4 NFE exome

AF:

0.000331

Gnomad4 OTH exome

AF:

0.000121

GnomAD4 genome

AF:

0.000105

AC:

AN:

152150

Hom.:

Cov.:

AF XY:

0.000108

AC XY:

AN XY:

74340

show subpopulations

Gnomad4 AFR

AF:

0.0000241

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:

0.000221

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000360

Hom.:

Bravo

AF:

0.000121

TwinsUK

AF:

0.00108

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.00145

AC:

ESP6500EA

AF:

0.000314

AC:

ExAC

AF:

0.0000599

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Autosomal recessive nonsyndromic hearing loss 77

Uncertain:2

Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Jan 17, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	May 23, 2018	- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Feb 26, 2015

The p.Lys1734Arg variant in LOXHD1 has not been previously reported in individua ls with hearing loss, but has been identified in 0.1% (2/2758) of African chromo somes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs370816148). Although this variant has been seen in the general populati on, its frequency is not high enough to rule out a pathogenic role. Computationa l prediction tools and conservation analysis do not provide strong support for o r against an impact to the protein. In summary, the clinical significance of the p.Lys1734Arg variant is uncertain. -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 12, 2023

The c.5201A>G (p.K1734R) alteration is located in exon 33 (coding exon 33) of the LOXHD1 gene. This alteration results from a A to G substitution at nucleotide position 5201, causing the lysine (K) at amino acid position 1734 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 18, 2021

This sequence change replaces lysine, which is basic and polar, with arginine, which is basic and polar, at codon 1734 of the LOXHD1 protein (p.Lys1734Arg). This variant is present in population databases (rs370816148, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with LOXHD1-related conditions. ClinVar contains an entry for this variant (Variation ID: 228831). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Hearing loss, autosomal recessive

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.19

BayesDel_addAF

Benign

-0.18

BayesDel_noAF

Benign

-0.22

CADD

Pathogenic

DANN

Uncertain

0.98

DEOGEN2

Benign

0.029

.;.;.;T;.;.;.;.;.;.

Eigen

Uncertain

0.53

Eigen_PC

Uncertain

0.57

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.90

D;D;D;D;D;D;D;D;D;D

M_CAP

Uncertain

0.12

MetaRNN

Benign

0.24

T;T;T;T;T;T;T;T;T;T

MetaSVM

Uncertain

-0.26

MutationTaster

Benign

0.99

D;D;D;D;D;D;D;D;D

PrimateAI

Benign

0.48

PROVEAN

Uncertain

-2.4

N;.;N;.;N;N;.;.;D;.

REVEL

Uncertain

0.30

Sift

Uncertain

0.023

D;.;D;.;T;D;.;.;D;.

Sift4G

Benign

0.25

T;D;T;D;D;T;.;D;.;.

Polyphen

1.0

.;.;.;.;D;.;.;.;.;.

Vest4

0.42

MVP

0.40

ClinPred

0.13

GERP RS

5.3

Varity_R

0.33

gMVP

0.37

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