rs376122149

Variant summary

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

The NM_001384474.1(LOXHD1):​c.5050G>T​(p.Ala1684Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 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. A1684T) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Consequence

LOXHD1
NM_001384474.1 missense

Scores

18

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.36

Publications

5 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

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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=0.11021426).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
LOXHD1NM_001384474.1 linkc.5050G>T p.Ala1684Ser missense_variant Exon 32 of 41 ENST00000642948.1 NP_001371403.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
LOXHD1ENST00000642948.1 linkc.5050G>T p.Ala1684Ser missense_variant Exon 32 of 41 NM_001384474.1 ENSP00000496347.1 A0A2R8Y7K4

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
31
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
-0.16
T
BayesDel_noAF
Benign
-0.46
CADD
Benign
17
DANN
Benign
0.94
DEOGEN2
Benign
0.0040
.;.;T;.;.;.
Eigen
Benign
-0.54
Eigen_PC
Benign
-0.44
FATHMM_MKL
Benign
0.097
N
LIST_S2
Benign
0.82
T;T;T;T;T;T
M_CAP
Benign
0.025
D
MetaRNN
Benign
0.11
T;T;T;T;T;T
MetaSVM
Benign
-0.92
T
PhyloP100
2.4
PrimateAI
Benign
0.34
T
PROVEAN
Benign
-0.040
.;N;.;N;.;.
REVEL
Benign
0.14
Sift
Benign
0.41
.;T;.;T;.;.
Sift4G
Benign
0.40
T;T;T;T;.;T
Polyphen
0.90
.;.;.;P;.;.
Vest4
0.22
MutPred
0.48
.;.;.;Gain of disorder (P = 0.0364);Gain of disorder (P = 0.0364);.;
MVP
0.16
ClinPred
0.77
D
GERP RS
5.0
Varity_R
0.044
gMVP
0.23

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.030
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: rs376122149; hg19: chr18-44102099; API