18-46538169-C-T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_StrongBP6

The NM_001384474.1(LOXHD1):c.4082G>A(p.Arg1361His) variant causes a missense change. The variant allele was found at a frequency of 0.0000627 in 1,532,162 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1361C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00034 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000033 ( 0 hom. )

Consequence

LOXHD1
NM_001384474.1 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5B:2

Conservation

PhyloP100: 3.92

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: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
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 -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.026607186).

BP6

Variant 18-46538169-C-T is Benign according to our data. Variant chr18-46538169-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 228825.

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	UniProt
LOXHD1	NM_001384474.1	MANE Select	c.4082G>A	p.Arg1361His	missense	Exon 26 of 41	NP_001371403.1	A0A2R8Y7K4
LOXHD1	NM_144612.7		c.4082G>A	p.Arg1361His	missense	Exon 26 of 40	NP_653213.6
LOXHD1	NM_001145472.3		c.749G>A	p.Arg250His	missense	Exon 8 of 24	NP_001138944.1	Q8IVV2-3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
LOXHD1	ENST00000642948.1	MANE Select	c.4082G>A	p.Arg1361His	missense	Exon 26 of 41	ENSP00000496347.1	A0A2R8Y7K4
LOXHD1	ENST00000300591.11	TSL:1	c.749G>A	p.Arg250His	missense	Exon 8 of 24	ENSP00000300591.6	Q8IVV2-3
LOXHD1	ENST00000579038.6	TSL:1	c.461G>A	p.Arg154His	missense	Exon 6 of 22	ENSP00000463285.1	J3QKX9

Frequencies

GnomAD3 genomes

AF:

0.000335

AC:

AN:

152174

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00116

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.000147

AC:

AN:

156156

AF XY:

0.0000972

show subpopulations

Gnomad AFR exome

AF:

0.00242

Gnomad AMR exome

AF:

0.0000809

Gnomad ASJ exome

AF:

0.00

Gnomad EAS 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:

0.0000326

AC:

AN:

1379988

Hom.:

Cov.:

AF XY:

0.0000400

AC XY:

AN XY:

675812

show subpopulations

African (AFR)

AF:

0.00102

AC:

AN:

31292

American (AMR)

AF:

0.0000282

AC:

AN:

35434

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24996

East Asian (EAS)

AF:

0.0000854

AC:

AN:

35110

South Asian (SAS)

AF:

0.00

AC:

AN:

78786

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49018

Middle Eastern (MID)

AF:

0.000180

AC:

AN:

5542

European-Non Finnish (NFE)

AF:

0.00000282

AC:

AN:

1062782

Other (OTH)

AF:

0.0000877

AC:

AN:

57028

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

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:

0.000335

AC:

AN:

152174

Hom.:

Cov.:

AF XY:

0.000377

AC XY:

AN XY:

74332

show subpopulations

African (AFR)

AF:

0.00116

AC:

AN:

41424

American (AMR)

AF:

0.0000655

AC:

AN:

15276

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.000192

AC:

AN:

5198

South Asian (SAS)

AF:

0.00

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68046

Other (OTH)

AF:

0.000478

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

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:

0.000348

Hom.:

Bravo

AF:

0.000472

ESP6500AA

AF:

0.00289

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000347

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Autosomal recessive nonsyndromic hearing loss 77 (2)

not provided (2)

Inborn genetic diseases (1)

LOXHD1-related disorder (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.093

BayesDel_addAF

Benign

-0.41

BayesDel_noAF

Benign

-0.37

CADD

Pathogenic

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.031

Eigen

Uncertain

0.58

Eigen_PC

Uncertain

0.58

FATHMM_MKL

Uncertain

0.83

LIST_S2

Uncertain

0.97

M_CAP

Benign

0.042

MetaRNN

Benign

0.027

MetaSVM

Benign

-0.35

PhyloP100

3.9

PrimateAI

Benign

0.25

PROVEAN

Benign

-1.8

REVEL

Uncertain

0.34

Sift

Benign

0.19

Sift4G

Benign

0.40

Polyphen

1.0

Vest4

0.29

MVP

0.28

ClinPred

0.095

GERP RS

5.4

Varity_R

0.070

gMVP

0.52

Mutation Taster

=75/25

polymorphism

(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

Computational scores

Splicing

Publications

Other links and lift over