18-46577834-G-C

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001384474.1(LOXHD1):c.1843C>G(p.Arg615Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000357 in 1,399,424 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R615Q) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000036 ( 0 hom. )

Consequence

LOXHD1
NM_001384474.1 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.880

Publications

6 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: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.15002319).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LOXHD1	NM_001384474.1 link	c.1843C>G	p.Arg615Gly	missense_variant	Exon 14 of 41	ENST00000642948.1	NP_001371403.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
LOXHD1	ENST00000642948.1 link	c.1843C>G	p.Arg615Gly	missense_variant	Exon 14 of 41		NM_001384474.1	ENSP00000496347.1	A0A2R8Y7K4
LOXHD1	ENST00000536736.5 link	c.1843C>G	p.Arg615Gly	missense_variant	Exon 14 of 40	5		ENSP00000444586.1	F5GZB4
LOXHD1	ENST00000441551.6 link	c.1843C>G	p.Arg615Gly	missense_variant	Exon 14 of 39	5		ENSP00000387621.2	Q8IVV2-1
LOXHD1	ENST00000335730.6 link	n.1156C>G		non_coding_transcript_exon_variant	Exon 7 of 27	2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000632

AC:

AN:

158190

AF XY:

0.0000120

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000164

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000357

AC:

AN:

1399424

Hom.:

Cov.:

AF XY:

0.00000580

AC XY:

AN XY:

690212

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31598

American (AMR)

AF:

0.00

AC:

AN:

35704

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25182

East Asian (EAS)

AF:

0.00

AC:

AN:

35738

South Asian (SAS)

AF:

0.00

AC:

AN:

79236

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49280

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5698

European-Non Finnish (NFE)

AF:

0.00000463

AC:

AN:

1078978

Other (OTH)

AF:

0.00

AC:

AN:

58010

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.37

BayesDel_addAF

Benign

-0.25

BayesDel_noAF

Benign

-0.59

CADD

Benign

8.4

(source)

DANN

Benign

0.63

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.73

LIST_S2

Benign

0.85

T;T;D

M_CAP

Benign

0.0099

MetaRNN

Benign

0.15

T;T;T

MetaSVM

Benign

-0.85

PhyloP100

0.88

PrimateAI

Benign

0.39

PROVEAN

Benign

-0.27

N;.;.

REVEL

Benign

0.086

Sift

Benign

0.31

T;.;.

Sift4G

Benign

0.40

T;.;T

Polyphen

0.0050

B;.;.

Vest4

0.24

MutPred

0.64

Loss of MoRF binding (P = 0.0213);Loss of MoRF binding (P = 0.0213);Loss of MoRF binding (P = 0.0213);

MVP

0.040

ClinPred

0.045

GERP RS

-2.1

Varity_R

0.16

gMVP

0.68

Mutation Taster

=81/19

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

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18-46577834-G-C

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over