18-46601290-A-T

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001384474.1(LOXHD1):c.1061T>A(p.Leu354His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000143 in 1,399,412 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

LOXHD1
NM_001384474.1 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:2

Conservation

PhyloP100: 9.29

Publications

0 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 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LOXHD1	NM_001384474.1 link	c.1061T>A	p.Leu354His	missense_variant	Exon 8 of 41	ENST00000642948.1	NP_001371403.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
LOXHD1	ENST00000642948.1 link	c.1061T>A	p.Leu354His	missense_variant	Exon 8 of 41		NM_001384474.1	ENSP00000496347.1	A0A2R8Y7K4
LOXHD1	ENST00000536736.5 link	c.1061T>A	p.Leu354His	missense_variant	Exon 8 of 40	5		ENSP00000444586.1	F5GZB4
LOXHD1	ENST00000441551.6 link	c.1061T>A	p.Leu354His	missense_variant	Exon 8 of 39	5		ENSP00000387621.2	Q8IVV2-1
LOXHD1	ENST00000335730.6 link	n.374T>A		non_coding_transcript_exon_variant	Exon 1 of 27	2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.0000126

AC:

AN:

158414

AF XY:

0.0000120

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000808

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:

0.00000143

AC:

AN:

1399412

Hom.:

Cov.:

AF XY:

0.00000145

AC XY:

AN XY:

690210

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31598

American (AMR)

AF:

0.0000560

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:

49278

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5698

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1078972

Other (OTH)

AF:

0.00

AC:

AN:

58006

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jul 01, 2014

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The Leu354His variant in LOXHD1 has not been previously reported in individuals with hearing loss and was absent from large population studies. Computational pr ediction tools and conservation analyses suggest that the Leu354His variant may impact the protein, though this information is not predictive enough to determin e pathogenicity. In summary, the clinical significance of the Leu354His variant is uncertain. -

Autosomal recessive nonsyndromic hearing loss 77

Uncertain:1

Oct 28, 2019

Natera, Inc.

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.80

BayesDel_addAF

Pathogenic

0.17

BayesDel_noAF

Pathogenic

0.19

CADD

Uncertain

(source)

DANN

Benign

0.90

Eigen

Uncertain

0.64

Eigen_PC

Pathogenic

0.66

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Benign

0.83

T;T;T

M_CAP

Benign

0.040

MetaRNN

Uncertain

0.73

D;D;D

MetaSVM

Benign

-0.59

PhyloP100

9.3

PrimateAI

Uncertain

0.73

PROVEAN

Uncertain

-2.8

D;.;.

REVEL

Uncertain

0.57

Sift

Uncertain

0.020

D;.;.

Sift4G

Pathogenic

0.0

D;.;D

Polyphen

1.0

D;.;.

Vest4

0.93

MutPred

0.53

Gain of disorder (P = 0.0206);Gain of disorder (P = 0.0206);Gain of disorder (P = 0.0206);

MVP

0.39

ClinPred

0.74

GERP RS

5.6

Varity_R

0.37

gMVP

0.45

Mutation Taster

=18/82

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over