GeneBe

rs727503139

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001384474.1(LOXHD1):​c.5273T>G​(p.Val1758Gly) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. 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. V1758F) has been classified as Uncertain significance.

Frequency

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

Consequence

LOXHD1
NM_001384474.1 missense, splice_region

Scores

1
7
9
Splicing: ADA: 0.001938
2

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 5.85

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: 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: Likely_benign. The variant received -2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.012496382).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
LOXHD1NM_001384474.1 linkc.5273T>G p.Val1758Gly missense_variant, splice_region_variant Exon 34 of 41 ENST00000642948.1 NP_001371403.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
LOXHD1ENST00000642948.1 linkc.5273T>G p.Val1758Gly missense_variant, splice_region_variant Exon 34 of 41 NM_001384474.1 ENSP00000496347.1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD2 exomes
AF:
0.000412
AC:
65
AN:
157592
AF XY:
0.000301
show subpopulations
Gnomad AFR exome
AF:
0.00341
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.000236
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.000297
Gnomad NFE exome
AF:
0.000446
Gnomad OTH exome
AF:
0.000448
GnomAD4 exome
Data not reliable, filtered out with message: AS_VQSR
AF:
7.15e-7
AC:
1
AN:
1398976
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
689960
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:
35696
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
25168
East Asian (EAS)
AF:
0.00
AC:
0
AN:
35730
South Asian (SAS)
AF:
0.00
AC:
0
AN:
79232
European-Finnish (FIN)
AF:
0.0000203
AC:
1
AN:
49238
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5694
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
1078636
Other (OTH)
AF:
0.00
AC:
0
AN:
57984
⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.275
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
GnomAD4 genome
Cov.:
32
ExAC
AF:
0.00381
AC:
102

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.41
BayesDel_addAF
Pathogenic
0.17
D
BayesDel_noAF
Uncertain
0.0
CADD
Uncertain
25
DANN
Benign
0.90
DEOGEN2
Benign
0.094
.;.;T;.;.;.
Eigen
Benign
0.11
Eigen_PC
Benign
0.080
FATHMM_MKL
Uncertain
0.94
D
LIST_S2
Benign
0.64
T;T;T;T;T;T
MetaRNN
Benign
0.0097
T;T;T;T;T;T
MetaSVM
Uncertain
-0.11
T
PhyloP100
5.8
PrimateAI
Uncertain
0.50
T
PROVEAN
Uncertain
-3.6
.;D;.;D;.;.
REVEL
Benign
0.23
Sift
Benign
0.045
.;D;.;D;.;.
Sift4G
Uncertain
0.0020
D;D;D;D;.;D
Polyphen
0.94
.;.;.;P;.;.
Vest4
0.36
MutPred
0.65
.;.;.;Loss of sheet (P = 0.0054);.;.;
MVP
0.48
ClinPred
0.13
T
GERP RS
2.5
Varity_R
0.13
gMVP
0.78

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Benign
0.0019
dbscSNV1_RF
Benign
0.082
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: rs727503139; hg19: chr18-44098218; API