NM_001384474.1:c.4868A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001384474.1(LOXHD1):​c.4868A>G​(p.Glu1623Gly) variant causes a missense change. The variant allele was found at a frequency of 0.0916 in 1,551,170 control chromosomes in the GnomAD database, including 7,016 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.071 ( 516 hom., cov: 33)
Exomes 𝑓: 0.094 ( 6500 hom. )

Consequence

LOXHD1
NM_001384474.1 missense

Scores

1
4
12

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 4.34

Publications

21 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: Benign. The variant received -20 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.0017565191).
BP6
Variant 18-46524474-T-C is Benign according to our data. Variant chr18-46524474-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 47941.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BA1
GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0983 is higher than 0.05.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
LOXHD1NM_001384474.1 linkc.4868A>G p.Glu1623Gly missense_variant Exon 31 of 41 ENST00000642948.1 NP_001371403.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
LOXHD1ENST00000642948.1 linkc.4868A>G p.Glu1623Gly missense_variant Exon 31 of 41 NM_001384474.1 ENSP00000496347.1 A0A2R8Y7K4

Frequencies

GnomAD3 genomes
AF:
0.0712
AC:
10835
AN:
152190
Hom.:
516
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.0227
Gnomad AMI
AF:
0.253
Gnomad AMR
AF:
0.0764
Gnomad ASJ
AF:
0.0934
Gnomad EAS
AF:
0.0594
Gnomad SAS
AF:
0.0738
Gnomad FIN
AF:
0.0444
Gnomad MID
AF:
0.0728
Gnomad NFE
AF:
0.100
Gnomad OTH
AF:
0.0937
GnomAD2 exomes
AF:
0.0767
AC:
12120
AN:
158082
AF XY:
0.0792
show subpopulations
Gnomad AFR exome
AF:
0.0233
Gnomad AMR exome
AF:
0.0530
Gnomad ASJ exome
AF:
0.0969
Gnomad EAS exome
AF:
0.0615
Gnomad FIN exome
AF:
0.0452
Gnomad NFE exome
AF:
0.101
Gnomad OTH exome
AF:
0.0900
GnomAD4 exome
AF:
0.0938
AC:
131206
AN:
1398862
Hom.:
6500
Cov.:
32
AF XY:
0.0938
AC XY:
64676
AN XY:
689818
show subpopulations
African (AFR)
AF:
0.0183
AC:
577
AN:
31588
American (AMR)
AF:
0.0551
AC:
1968
AN:
35694
Ashkenazi Jewish (ASJ)
AF:
0.0955
AC:
2405
AN:
25182
East Asian (EAS)
AF:
0.0396
AC:
1415
AN:
35722
South Asian (SAS)
AF:
0.0800
AC:
6335
AN:
79228
European-Finnish (FIN)
AF:
0.0486
AC:
2397
AN:
49272
Middle Eastern (MID)
AF:
0.0748
AC:
426
AN:
5696
European-Non Finnish (NFE)
AF:
0.102
AC:
110396
AN:
1078516
Other (OTH)
AF:
0.0912
AC:
5287
AN:
57964
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.487
Heterozygous variant carriers
0
7157
14313
21470
28626
35783
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Exome Hom
Variant carriers
0
4046
8092
12138
16184
20230
<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
AF:
0.0711
AC:
10829
AN:
152308
Hom.:
516
Cov.:
33
AF XY:
0.0690
AC XY:
5140
AN XY:
74476
show subpopulations
African (AFR)
AF:
0.0226
AC:
941
AN:
41570
American (AMR)
AF:
0.0763
AC:
1167
AN:
15302
Ashkenazi Jewish (ASJ)
AF:
0.0934
AC:
324
AN:
3470
East Asian (EAS)
AF:
0.0588
AC:
305
AN:
5186
South Asian (SAS)
AF:
0.0734
AC:
354
AN:
4822
European-Finnish (FIN)
AF:
0.0444
AC:
472
AN:
10628
Middle Eastern (MID)
AF:
0.0748
AC:
22
AN:
294
European-Non Finnish (NFE)
AF:
0.100
AC:
6818
AN:
68012
Other (OTH)
AF:
0.0927
AC:
196
AN:
2114
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.501
Heterozygous variant carriers
0
518
1036
1554
2072
2590
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Genome Hom
Variant carriers
0
132
264
396
528
660
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
Alfa
AF:
0.0910
Hom.:
2937
Bravo
AF:
0.0711
TwinsUK
AF:
0.103
AC:
381
ALSPAC
AF:
0.0986
AC:
380
ESP6500AA
AF:
0.0260
AC:
36
ESP6500EA
AF:
0.115
AC:
366
ExAC
AF:
0.0742
AC:
1881
Asia WGS
AF:
0.0590
AC:
204
AN:
3478

ClinVar

Significance: Benign/Likely benign
Submissions summary: Benign:8
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Benign:3
-
PreventionGenetics, part of Exact Sciences
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

May 07, 2012
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

Glu1623Gly in Exon 31 of LOXHD1: This variant is not expected to have clinical s ignificance because it has been identified in 11.1% (281/2532) of European Ameri can chromosomes from a broad population by the NHLBI Exome Sequencing Project (h ttp://evs.gs.washington.edu/EVS; dbSNP rs12606417). -

May 09, 2017
GeneDx
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Autosomal recessive nonsyndromic hearing loss 77 Benign:3
Sep 16, 2020
Natera, Inc.
Significance:Benign
Review Status:no assertion criteria provided
Collection Method:clinical testing

- -

Jan 13, 2018
Illumina Laboratory Services, Illumina
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Jul 10, 2021
Genome-Nilou Lab
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

not provided Benign:2
Feb 03, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

-
Breakthrough Genomics, Breakthrough Genomics
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.14
BayesDel_addAF
Benign
-0.57
T
BayesDel_noAF
Benign
-0.50
CADD
Uncertain
26
DANN
Uncertain
0.98
DEOGEN2
Benign
0.074
.;.;T;.;.;T
Eigen
Benign
-0.0081
Eigen_PC
Benign
0.088
FATHMM_MKL
Pathogenic
0.97
D
LIST_S2
Uncertain
0.87
D;D;D;D;D;D
MetaRNN
Benign
0.0018
T;T;T;T;T;T
MetaSVM
Benign
-1.1
T
PhyloP100
4.3
PrimateAI
Benign
0.38
T
PROVEAN
Uncertain
-3.1
.;D;.;D;.;.
REVEL
Benign
0.069
Sift
Benign
0.055
.;T;.;T;.;.
Sift4G
Uncertain
0.057
T;T;D;D;.;T
Polyphen
0.97
.;.;.;D;.;.
Vest4
0.19
ClinPred
0.034
T
GERP RS
5.1
Varity_R
0.65
gMVP
0.45
Mutation Taster
=86/14
polymorphism (auto)

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: rs12606417; hg19: chr18-44104437; COSMIC: COSV56061462; COSMIC: COSV56061462; API