rs373924055

Variant names:

• chr18-46518215-G-A
• rs373924055
• NM_001384474.1:c.5313C>T

Your query was ambiguous. Multiple possible variants found:

• chr18-46518215-G-A
• chr18-46518215-G-C

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6 BP7

The NM_001384474.1(LOXHD1):​c.5313C>T​(p.Gly1771Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00192 in 1,551,576 control chromosomes in the GnomAD database, including 1 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 0.0016 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0020 (1 hom.)
• Consequence: LOXHD1 NM_001384474.1 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:8
• Conservation: PhyloP100: -2.62

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]

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.68).
• BP6: Variant 18-46518215-G-A is Benign according to our data. Variant chr18-46518215-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 47943.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Benign=2, Uncertain_significance=2}.
• BP7: Synonymous conserved (PhyloP=-2.62 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LOXHD1	NM_001384474.1	c.5313C>T	p.Gly1771Gly	synonymous_variant	Exon 34 of 41	ENST00000642948.1	NP_001371403.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LOXHD1	ENST00000642948.1	c.5313C>T	p.Gly1771Gly	synonymous_variant	Exon 34 of 41		NM_001384474.1	ENSP00000496347.1

Frequencies

GnomAD3 genomes AF: 0.00159 AC: 242 AN: 152078 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000459

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00111

Gnomad ASJ AF: 0.00346

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00123

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00257

Gnomad OTH AF: 0.00240

GnomAD3 exomes AF: 0.00152 AC: 240 AN: 158388 Hom.: 0 AF XY: 0.00161 AC XY: 134 AN XY: 83446

Gnomad AFR exome AF: 0.000115

Gnomad AMR exome AF: 0.00113

Gnomad ASJ exome AF: 0.00376

Gnomad EAS exome AF: 0.0000884

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00171

Gnomad NFE exome AF: 0.00226

Gnomad OTH exome AF: 0.00246

GnomAD4 exome AF: 0.00195 AC: 2731 AN: 1399382 Hom.: 1 Cov.: 32 AF XY: 0.00191 AC XY: 1321 AN XY: 690190

Gnomad4 AFR exome AF: 0.000285

Gnomad4 AMR exome AF: 0.00129

Gnomad4 ASJ exome AF: 0.00338

Gnomad4 EAS exome AF: 0.0000839

Gnomad4 SAS exome AF: 0.0000252

Gnomad4 FIN exome AF: 0.00173

Gnomad4 NFE exome AF: 0.00223

Gnomad4 OTH exome AF: 0.00164

GnomAD4 genome AF: 0.00159 AC: 242 AN: 152194 Hom.: 0 Cov.: 32 AF XY: 0.00140 AC XY: 104 AN XY: 74410

Gnomad4 AFR AF: 0.000458

Gnomad4 AMR AF: 0.00111

Gnomad4 ASJ AF: 0.00346

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00123

Gnomad4 NFE AF: 0.00257

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.00236 Hom.: 0

Bravo AF: 0.00138

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:8

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:4

Mar 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

LOXHD1: BP4, BP7 -

Dec 24, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 05, 2019

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 17, 2018

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 02, 2016

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Autosomal recessive nonsyndromic hearing loss 77 Uncertain:1 Benign:2

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Jun 29, 2020

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Mar 27, 2017

Counsyl

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

Jan 28, 2015

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

p.Gly1709Gly in exon 33 of LOXHD1: This variant is not expected to have clinical significance because it does not alter an amino acid residue, is not located wi thin the splice consensus sequence, and has been identified in 0.2% (18/8740) of European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.bro adinstitute.org). -

LOXHD1-related disorder Benign:1

Oct 15, 2019

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.68
CADD	Benign	1.1
DANN	Benign	0.53

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

Other links and lift over

dbSNP: rs373924055; hg19: chr18-44098178; COSMIC: COSV56060844;