rs775871086

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.5458A>T(p.Thr1820Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000102 in 1,551,276 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000092 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00010 ( 1 hom. )

Consequence

LOXHD1
NM_001384474.1 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:1

Conservation

PhyloP100: 6.16

Publications

3 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=0.051597178).

BP6

Variant 18-46509757-T-A is Benign according to our data. Variant chr18-46509757-T-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 228834.

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.5458A>T	p.Thr1820Ser	missense	Exon 35 of 41	NP_001371403.1	A0A2R8Y7K4
LOXHD1	NM_144612.7		c.5272A>T	p.Thr1758Ser	missense	Exon 34 of 40	NP_653213.6
LOXHD1	NM_001145472.3		c.2125A>T	p.Thr709Ser	missense	Exon 17 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.5458A>T	p.Thr1820Ser	missense	Exon 35 of 41	ENSP00000496347.1	A0A2R8Y7K4
LOXHD1	ENST00000300591.11	TSL:1	c.2125A>T	p.Thr709Ser	missense	Exon 17 of 24	ENSP00000300591.6	Q8IVV2-3
LOXHD1	ENST00000579038.6	TSL:1	c.1837A>T	p.Thr613Ser	missense	Exon 15 of 22	ENSP00000463285.1	J3QKX9

Frequencies

GnomAD3 genomes

AF:

0.0000922

AC:

AN:

151842

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000328

Gnomad ASJ

AF:

0.00173

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000208

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000297

AC:

AN:

158434

AF XY:

0.000324

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000889

Gnomad ASJ exome

AF:

0.00224

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000164

Gnomad OTH exome

AF:

0.000224

GnomAD4 exome

AF:

0.000103

AC:

144

AN:

1399316

Hom.:

Cov.:

AF XY:

0.000106

AC XY:

AN XY:

690158

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31596

American (AMR)

AF:

0.000868

AC:

AN:

35704

Ashkenazi Jewish (ASJ)

AF:

0.00206

AC:

AN:

25182

East Asian (EAS)

AF:

0.00

AC:

AN:

35738

South Asian (SAS)

AF:

0.000215

AC:

AN:

79228

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49278

Middle Eastern (MID)

AF:

0.000355

AC:

AN:

5630

European-Non Finnish (NFE)

AF:

0.0000297

AC:

AN:

1078970

Other (OTH)

AF:

0.000172

AC:

AN:

57990

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.469

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:

0.0000921

AC:

AN:

151960

Hom.:

Cov.:

AF XY:

0.000108

AC XY:

AN XY:

74264

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41426

American (AMR)

AF:

0.000328

AC:

AN:

15254

Ashkenazi Jewish (ASJ)

AF:

0.00173

AC:

AN:

3464

East Asian (EAS)

AF:

0.00

AC:

AN:

5166

South Asian (SAS)

AF:

0.000208

AC:

AN:

4802

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10538

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

67990

Other (OTH)

AF:

0.00

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.468

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:

0.000293

Hom.:

ExAC

AF:

0.000223

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 (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.18

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.41

CADD

Uncertain

(source)

DANN

Benign

0.93

DEOGEN2

Benign

0.0083

Eigen

Uncertain

0.32

Eigen_PC

Uncertain

0.42

FATHMM_MKL

Uncertain

0.97

LIST_S2

Uncertain

0.95

M_CAP

Benign

0.039

MetaRNN

Benign

0.052

MetaSVM

Benign

-0.46

PhyloP100

6.2

PrimateAI

Uncertain

0.54

PROVEAN

Benign

-0.68

REVEL

Benign

0.17

Sift

Benign

0.36

Sift4G

Benign

0.23

Polyphen

0.63

Vest4

0.34

MutPred

0.48

Loss of helix (P = 0.0138)

MVP

0.27

ClinPred

0.076

GERP RS

5.5

Varity_R

0.12

gMVP

0.17

Mutation Taster

=78/22

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