NM_001384474.1:c.1815C>G

Variant summary

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

The NM_001384474.1(LOXHD1):​c.1815C>G​(p.Asp605Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000715 in 1,399,380 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. D605D) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 7.1e-7 ( 0 hom. )

Consequence

LOXHD1
NM_001384474.1 missense

Scores

3
8
6

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.0140

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

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
LOXHD1NM_001384474.1 linkc.1815C>G p.Asp605Glu missense_variant Exon 14 of 41 ENST00000642948.1 NP_001371403.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
LOXHD1ENST00000642948.1 linkc.1815C>G p.Asp605Glu missense_variant Exon 14 of 41 NM_001384474.1 ENSP00000496347.1 A0A2R8Y7K4
LOXHD1ENST00000536736.5 linkc.1815C>G p.Asp605Glu missense_variant Exon 14 of 40 5 ENSP00000444586.1 F5GZB4
LOXHD1ENST00000441551.6 linkc.1815C>G p.Asp605Glu missense_variant Exon 14 of 39 5 ENSP00000387621.2 Q8IVV2-1
LOXHD1ENST00000335730.6 linkn.1128C>G non_coding_transcript_exon_variant Exon 7 of 27 2

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
7.15e-7
AC:
1
AN:
1399380
Hom.:
0
Cov.:
31
AF XY:
0.00
AC XY:
0
AN XY:
690198
show subpopulations
⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.
African (AFR)
AF:
0.00
AC:
0
AN:
31598
American (AMR)
AF:
0.00
AC:
0
AN:
35702
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
25182
East Asian (EAS)
AF:
0.00
AC:
0
AN:
35738
South Asian (SAS)
AF:
0.00
AC:
0
AN:
79236
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
49250
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5698
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
1078970
Other (OTH)
AF:
0.0000172
AC:
1
AN:
58006
⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.375
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
2
4
6
8
10
<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
Cov.:
32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.88
BayesDel_addAF
Uncertain
0.12
D
BayesDel_noAF
Uncertain
-0.060
CADD
Benign
1.2
DANN
Benign
0.46
Eigen
Benign
-0.98
Eigen_PC
Benign
-1.2
FATHMM_MKL
Benign
0.38
N
LIST_S2
Uncertain
0.91
D;D;D
M_CAP
Benign
0.030
D
MetaRNN
Uncertain
0.63
D;D;D
MetaSVM
Uncertain
0.20
D
PhyloP100
-0.014
PrimateAI
Uncertain
0.65
T
PROVEAN
Uncertain
-3.6
D;.;.
REVEL
Uncertain
0.43
Sift
Pathogenic
0.0
D;.;.
Sift4G
Pathogenic
0.0
D;.;D
Polyphen
1.0
D;.;.
Vest4
0.73
MutPred
0.46
Loss of ubiquitination at K601 (P = 0.0709);Loss of ubiquitination at K601 (P = 0.0709);Loss of ubiquitination at K601 (P = 0.0709);
MVP
0.014
ClinPred
0.98
D
GERP RS
-9.6
Varity_R
0.16
gMVP
0.77
Mutation Taster
=66/34
polymorphism

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

Other links and lift over

dbSNP: rs201388780; hg19: chr18-44157825; API