18-46559498-C-T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP4

The NM_001384474.1(LOXHD1):c.3166G>A(p.Glu1056Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000825 in 1,551,880 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. E1056E) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00012 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000078 ( 0 hom. )

Consequence

LOXHD1
NM_001384474.1 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:2

Conservation

PhyloP100: 7.87

Publications

2 publications found

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 Gene-Disease associations (from GenCC):

autosomal recessive nonsyndromic hearing loss 77
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, PanelApp Australia, Labcorp Genetics (formerly Invitae), Ambry Genetics
nonsyndromic genetic hearing loss
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
hearing loss, autosomal recessive
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
Fuchs' endothelial dystrophy
Inheritance: AD Classification: LIMITED Submitted by: Illumina

LOXHD1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -1 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.40628457).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001384474.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
LOXHD1	NM_001384474.1	MANE Select	c.3166G>A	p.Glu1056Lys	missense	Exon 20 of 41	NP_001371403.1
LOXHD1	NM_144612.7		c.3166G>A	p.Glu1056Lys	missense	Exon 20 of 40	NP_653213.6
LOXHD1	NM_001145472.3		c.-600G>A		upstream_gene	N/A	NP_001138944.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
LOXHD1	ENST00000642948.1	MANE Select	c.3166G>A	p.Glu1056Lys	missense	Exon 20 of 41	ENSP00000496347.1
LOXHD1	ENST00000536736.5	TSL:5	c.3166G>A	p.Glu1056Lys	missense	Exon 20 of 40	ENSP00000444586.1
LOXHD1	ENST00000335730.6	TSL:2	n.2479G>A		non_coding_transcript_exon	Exon 13 of 27

Frequencies

GnomAD3 genomes

AF:

0.000125

AC:

AN:

152180

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000217

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:

0.000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000564

AC:

AN:

159554

AF XY:

0.0000477

show subpopulations

Gnomad AFR exome

AF:

0.000113

Gnomad AMR exome

AF:

0.0000404

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000113

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000779

AC:

109

AN:

1399700

Hom.:

Cov.:

AF XY:

0.0000869

AC XY:

AN XY:

690356

show subpopulations

African (AFR)

AF:

0.0000949

AC:

AN:

31598

American (AMR)

AF:

0.0000280

AC:

AN:

35706

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25182

East Asian (EAS)

AF:

0.00

AC:

AN:

35738

South Asian (SAS)

AF:

0.0000631

AC:

AN:

79230

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49436

Middle Eastern (MID)

AF:

0.000176

AC:

AN:

5698

European-Non Finnish (NFE)

AF:

0.0000908

AC:

AN:

1079038

Other (OTH)

AF:

0.0000172

AC:

AN:

58074

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.451

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000125

AC:

AN:

152180

Hom.:

Cov.:

AF XY:

0.000108

AC XY:

AN XY:

74324

show subpopulations

African (AFR)

AF:

0.000217

AC:

AN:

41448

American (AMR)

AF:

0.00

AC:

AN:

15276

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5190

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000147

AC:

AN:

68034

Other (OTH)

AF:

0.00

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000772

Hom.:

Bravo

AF:

0.0000945

ESP6500AA

AF:

0.000723

AC:

ESP6500EA

AF:

0.000314

AC:

ExAC

AF:

0.0000379

AC:

ClinVar

ClinVar submissions as Germline

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Autosomal recessive nonsyndromic hearing loss 77 (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.64

BayesDel_addAF

Uncertain

0.015

BayesDel_noAF

Uncertain

-0.010

CADD

Uncertain

(source)

DANN

Pathogenic

1.0

Eigen

Uncertain

0.33

Eigen_PC

Uncertain

0.38

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.77

M_CAP

Benign

0.033

MetaRNN

Benign

0.41

MetaSVM

Benign

-0.59

PhyloP100

7.9

PrimateAI

Uncertain

0.70

PROVEAN

Uncertain

-3.0

REVEL

Uncertain

0.38

Sift

Benign

0.033

Sift4G

Uncertain

0.014

Polyphen

0.96

Vest4

0.72

MVP

0.26

ClinPred

0.42

GERP RS

5.3

PromoterAI

0.0020

Neutral

(source)

gMVP

0.58

Mutation Taster

=45/55

disease causing

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over