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rs727503144

chr18-46559502-C-T

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 2P and 13B. PM2BP4_StrongBP6_Very_StrongBP7

The NM_001384474.1(LOXHD1):c.3162G>A(p.Thr1054=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000271 in 1,399,796 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. T1054T) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.000027 ( 0 hom. )

Consequence

LOXHD1
NM_001384474.1 synonymous

Scores

2

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -3.41
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 -11 ACMG points.

PM2
?
    PM2 - Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium
Very rare variant in population databases, with high coverage;
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=-0.85).
BP6
?
    BP6 - Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation
Variant 18-46559502-C-T is Benign according to our data. Variant chr18-46559502-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 163917.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr18-46559502-C-T is described in Lovd as [Likely_benign].
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=-3.41 with no splicing effect.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
LOXHD1NM_001384474.1 linkuse as main transcriptc.3162G>A p.Thr1054= synonymous_variant 20/41 ENST00000642948.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
LOXHD1ENST00000642948.1 linkuse as main transcriptc.3162G>A p.Thr1054= synonymous_variant 20/41 NM_001384474.1 P1
LOXHD1ENST00000536736.5 linkuse as main transcriptc.3162G>A p.Thr1054= synonymous_variant 20/405
LOXHD1ENST00000441551.6 linkuse as main transcriptc.2599-2013G>A intron_variant 5 Q8IVV2-1
LOXHD1ENST00000335730.6 linkuse as main transcriptn.2475G>A non_coding_transcript_exon_variant 13/272

Frequencies

GnomAD3 genomes
?
    Genome Aggregation Database, over 76,156 genomes
Cov.:
32
GnomAD3 exomes
AF:
0.0000250
AC:
4
AN:
159840
Hom.:
0
AF XY:
0.0000119
AC XY:
1
AN XY:
83944
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000484
Gnomad OTH exome
AF:
0.000220
GnomAD4 exome
AF:
0.0000271
AC:
38
AN:
1399796
Hom.:
0
Cov.:
32
AF XY:
0.0000246
AC XY:
17
AN XY:
690396
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000250
Gnomad4 OTH exome
AF:
0.000172
GnomAD4 genome
?
    Genome Aggregation Database, over 76,156 genomes
Cov.:
32
Alfa
AF:
0.000113
Hom.:
0

ClinVar

Significance: Likely benign
Submissions summary: Benign:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Benign:1
Likely benign, criteria provided, single submitterclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineJun 05, 2014Thr1054Thr in exon 20 of LOXHD1: This variant is not expected to have clinical s ignificance because it does not alter an amino acid residue and is not located w ithin the splice consensus sequence. -
Autosomal recessive nonsyndromic hearing loss 77 Benign:1
Likely benign, criteria provided, single submitterclinical testingCounsylJun 29, 2017- -
not provided Benign:1
Likely benign, criteria provided, single submitterclinical testingInvitaeJan 07, 2024- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.85
Cadd
Benign
0.071
Dann
Benign
0.68

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: rs727503144; hg19: chr18-44139465; API