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rs115658952

chr18-46566387-G-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_ModerateBP6BP7BS1BS2

The NM_001384474.1(LOXHD1):c.2307C>T(p.Ser769=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000471 in 1,551,540 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0025 ( 2 hom., cov: 33)
Exomes 𝑓: 0.00025 ( 0 hom. )

Consequence

LOXHD1
NM_001384474.1 synonymous

Scores

2

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:2

Conservation

PhyloP100: -0.536
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]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -12 ACMG points.

BP4
?
    BP4 - Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc.)
Computational evidence support a benign effect (BayesDel_noAF=-0.45).
BP6
?
    BP6 - Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation
Variant 18-46566387-G-A is Benign according to our data. Variant chr18-46566387-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 226713.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Benign=2}.
BP7
?
    BP7 - A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved
Synonymous conserved (PhyloP=-0.536 with no splicing effect.
BS1
?
    BS1 - Allele frequency is greater than expected for disorder
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00248 (378/152332) while in subpopulation AFR AF= 0.00852 (354/41572). AF 95% confidence interval is 0.00778. There are 2 homozygotes in gnomad4. There are 162 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
BS2
?
    BS2 - Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age
High Homozygotes in GnomAd at 2 AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
LOXHD1NM_001384474.1 linkuse as main transcriptc.2307C>T p.Ser769= synonymous_variant 17/41 ENST00000642948.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
LOXHD1ENST00000642948.1 linkuse as main transcriptc.2307C>T p.Ser769= synonymous_variant 17/41 NM_001384474.1 P1
LOXHD1ENST00000536736.5 linkuse as main transcriptc.2307C>T p.Ser769= synonymous_variant 17/405
LOXHD1ENST00000441551.6 linkuse as main transcriptc.2307C>T p.Ser769= synonymous_variant 17/395 Q8IVV2-1
LOXHD1ENST00000335730.6 linkuse as main transcriptn.1620C>T non_coding_transcript_exon_variant 10/272

Frequencies

GnomAD3 genomes
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.00248
AC:
377
AN:
152214
Hom.:
2
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00854
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000982
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.000192
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.00287
GnomAD3 exomes
AF:
0.000455
AC:
72
AN:
158264
Hom.:
0
AF XY:
0.000372
AC XY:
31
AN XY:
83416
show subpopulations
Gnomad AFR exome
AF:
0.00749
Gnomad AMR exome
AF:
0.000162
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000439
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000328
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.000252
AC:
353
AN:
1399208
Hom.:
0
Cov.:
31
AF XY:
0.000213
AC XY:
147
AN XY:
690106
show subpopulations
Gnomad4 AFR exome
AF:
0.00886
Gnomad4 AMR exome
AF:
0.000224
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000280
Gnomad4 SAS exome
AF:
0.0000252
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000334
Gnomad4 OTH exome
AF:
0.000448
GnomAD4 genome
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.00248
AC:
378
AN:
152332
Hom.:
2
Cov.:
33
AF XY:
0.00217
AC XY:
162
AN XY:
74502
show subpopulations
Gnomad4 AFR
AF:
0.00852
Gnomad4 AMR
AF:
0.000980
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.000193
Gnomad4 SAS
AF:
0.000207
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.00284
Alfa
AF:
0.00145
Hom.:
0
Bravo
AF:
0.00262
Asia WGS
AF:
0.000289
AC:
1
AN:
3478

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:2
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Autosomal recessive nonsyndromic hearing loss 77 Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaApr 27, 2017This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
not specified Benign:1
Benign, criteria provided, single submitterclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineMay 28, 2015p.Ser769Ser in exon 17 of LOXHD1: This variant is not expected to have clinical significance because it does not alter an amino acid residue, is not located wit hin the splice consensus sequence, and has been identified in 0.9% (24/2694) of African chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broad institute.org). -
not provided Benign:1
Benign, criteria provided, single submitterclinical testingInvitaeJan 31, 2024- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.45
Cadd
Benign
0.96
Dann
Benign
0.75

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs115658952; hg19: chr18-44146350; API