chr18-46656943-C-A

Variant summary

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

The NM_001384474.1(LOXHD1):​c.91G>T​(p.Asp31Tyr) 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 1,399,306 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/20 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. D31H) has been classified as Uncertain significance.

Frequency

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

Consequence

LOXHD1
NM_001384474.1 missense

Scores

1
16

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.780

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 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.089879245).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
LOXHD1NM_001384474.1 linkc.91G>T p.Asp31Tyr missense_variant Exon 1 of 41 ENST00000642948.1 NP_001371403.1
LOXHD1NM_144612.7 linkc.91G>T p.Asp31Tyr missense_variant Exon 1 of 40 NP_653213.6 Q8IVV2F5GZB4B7Z7T7

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
LOXHD1ENST00000642948.1 linkc.91G>T p.Asp31Tyr missense_variant Exon 1 of 41 NM_001384474.1 ENSP00000496347.1 A0A2R8Y7K4
LOXHD1ENST00000536736.5 linkc.91G>T p.Asp31Tyr missense_variant Exon 1 of 40 5 ENSP00000444586.1 F5GZB4
LOXHD1ENST00000441551.6 linkc.91G>T p.Asp31Tyr missense_variant Exon 1 of 39 5 ENSP00000387621.2 Q8IVV2-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
7.15e-7
AC:
1
AN:
1399306
Hom.:
0
Cov.:
31
AF XY:
0.00
AC XY:
0
AN XY:
690178
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
31598
American (AMR)
AF:
0.00
AC:
0
AN:
35692
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
25174
East Asian (EAS)
AF:
0.00
AC:
0
AN:
35738
South Asian (SAS)
AF:
0.00
AC:
0
AN:
79232
European-Finnish (FIN)
AF:
0.0000203
AC:
1
AN:
49280
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5696
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
1078910
Other (OTH)
AF:
0.00
AC:
0
AN:
57986
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.675
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

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.13
BayesDel_addAF
Benign
-0.28
T
BayesDel_noAF
Benign
-0.64
CADD
Benign
18
DANN
Benign
0.77
Eigen
Benign
-0.40
Eigen_PC
Benign
-0.48
FATHMM_MKL
Benign
0.094
N
LIST_S2
Benign
0.76
T;T;T
M_CAP
Benign
0.016
T
MetaRNN
Benign
0.090
T;T;T
MetaSVM
Benign
-1.0
T
PhyloP100
0.78
PrimateAI
Benign
0.39
T
PROVEAN
Benign
-1.1
N;.;.
REVEL
Benign
0.039
Sift
Benign
0.062
T;.;.
Sift4G
Uncertain
0.060
T;.;T
Polyphen
0.97
D;.;.
Vest4
0.31
MutPred
0.30
Loss of loop (P = 0.0128);Loss of loop (P = 0.0128);Loss of loop (P = 0.0128);
MVP
0.12
ClinPred
0.25
T
GERP RS
1.6
PromoterAI
-0.043
Neutral
Varity_R
0.075
gMVP
0.85
Mutation Taster
=92/8
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: rs876657862; hg19: chr18-44236906; API