18-46560448-C-T

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM5BP4_Moderate

The NM_001384474.1(LOXHD1):c.2696G>A(p.Arg899Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000013 in 1,543,534 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R899P) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000011 ( 0 hom. )

Consequence

LOXHD1
NM_001384474.1 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 2.74

Publications

7 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: Uncertain_significance. The variant received 0 ACMG points.

PM5

Other missense variant is known to change same aminoacid residue: Variant chr18-46560448-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 228819.

BP4

Computational evidence support a benign effect (MetaRNN=0.24197745).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LOXHD1	NM_001384474.1	MANE Select	c.2696G>A	p.Arg899Gln	missense	Exon 19 of 41	NP_001371403.1	A0A2R8Y7K4
	LOXHD1	NM_144612.7		c.2696G>A	p.Arg899Gln	missense	Exon 19 of 40	NP_653213.6

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
LOXHD1	ENST00000642948.1	MANE Select	c.2696G>A	p.Arg899Gln	missense	Exon 19 of 41	ENSP00000496347.1	A0A2R8Y7K4
LOXHD1	ENST00000536736.5	TSL:5	c.2696G>A	p.Arg899Gln	missense	Exon 19 of 40	ENSP00000444586.1	F5GZB4
LOXHD1	ENST00000441551.6	TSL:5	c.2598+2617G>A		intron	N/A	ENSP00000387621.2	Q8IVV2-1

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152186

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000266

AC:

AN:

150590

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000162

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:

0.0000115

AC:

AN:

1391348

Hom.:

Cov.:

AF XY:

0.00000728

AC XY:

AN XY:

686620

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31600

American (AMR)

AF:

0.000112

AC:

AN:

35706

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25180

East Asian (EAS)

AF:

0.00

AC:

AN:

35740

South Asian (SAS)

AF:

0.0000126

AC:

AN:

79234

European-Finnish (FIN)

AF:

0.00

AC:

AN:

41248

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5696

European-Non Finnish (NFE)

AF:

0.0000102

AC:

AN:

1078970

Other (OTH)

AF:

0.00

AC:

AN:

57974

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

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:

0.0000263

AC:

AN:

152186

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74348

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41448

American (AMR)

AF:

0.000131

AC:

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5170

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68028

Other (OTH)

AF:

0.00

AC:

AN:

2090

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

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000151

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Autosomal recessive nonsyndromic hearing loss 77 (1)

not provided (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.26

BayesDel_noAF

Benign

-0.35

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

Eigen

Benign

0.13

Eigen_PC

Benign

0.21

FATHMM_MKL

Benign

0.75

LIST_S2

Benign

0.85

M_CAP

Benign

0.055

MetaRNN

Benign

0.24

MetaSVM

Benign

-0.99

PhyloP100

2.7

PrimateAI

Benign

0.35

PROVEAN

Benign

-1.1

REVEL

Benign

0.16

Sift

Benign

0.048

Sift4G

Uncertain

0.017

Polyphen

0.94

Vest4

0.46

MutPred

0.56

Gain of catalytic residue at R899 (P = 0.0374)

MVP

0.15

ClinPred

0.32

GERP RS

4.1

gMVP

0.45

Mutation Taster

=80/20

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.15

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over