chr18-46485102-G-A

Position:

chr18-46485102-G-A

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP6BS1BS2

The NM_001384474.1(LOXHD1):c.6099C>T(p.Asn2033=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00189 in 1,549,766 control chromosomes in the GnomAD database, including 32 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 0.0014 ( 4 hom., cov: 30)

Exomes 𝑓: 0.0019 ( 28 hom. )

Consequence

LOXHD1
NM_001384474.1 synonymous

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:5

Conservation

PhyloP100: -0.139

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP6

Variant 18-46485102-G-A is Benign according to our data. Variant chr18-46485102-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 178392.We mark this variant Likely_benign, oryginal submissions are: {Benign=4, Uncertain_significance=1}.

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00144 (217/150330) while in subpopulation SAS AF= 0.0128 (59/4626). AF 95% confidence interval is 0.0102. There are 4 homozygotes in gnomad4. There are 119 alleles in male gnomad4 subpopulation. Median coverage is 30. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LOXHD1	NM_001384474.1 linkuse as main transcript	c.6099C>T	p.Asn2033=	synonymous_variant	39/41	ENST00000642948.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LOXHD1	ENST00000642948.1 linkuse as main transcript	c.6099C>T	p.Asn2033=	synonymous_variant	39/41		NM_001384474.1	P1

Frequencies

GnomAD3 genomes

AF:

0.00142

AC:

213

AN:

150212

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000197

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000669

Gnomad ASJ

AF:

0.000290

Gnomad EAS

AF:

0.00802

Gnomad SAS

AF:

0.0119

Gnomad FIN

AF:

0.000290

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00136

Gnomad OTH

AF:

0.00145

GnomAD3 exomes

AF:

0.00342

AC:

540

AN:

158032

Hom.:

AF XY:

0.00407

AC XY:

340

AN XY:

83438

show subpopulations

Gnomad AFR exome

AF:

0.000244

Gnomad AMR exome

AF:

0.000810

Gnomad ASJ exome

AF:

0.000822

Gnomad EAS exome

AF:

0.0127

Gnomad SAS exome

AF:

0.0116

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00154

Gnomad OTH exome

AF:

0.00290

GnomAD4 exome

AF:

0.00193

AC:

2706

AN:

1399436

Hom.:

Cov.:

AF XY:

0.00226

AC XY:

1561

AN XY:

690234

show subpopulations

Gnomad4 AFR exome

AF:

0.000253

Gnomad4 AMR exome

AF:

0.000840

Gnomad4 ASJ exome

AF:

0.000596

Gnomad4 EAS exome

AF:

0.00521

Gnomad4 SAS exome

AF:

0.0113

Gnomad4 FIN exome

AF:

0.000142

Gnomad4 NFE exome

AF:

0.00126

Gnomad4 OTH exome

AF:

0.00255

GnomAD4 genome

AF:

0.00144

AC:

217

AN:

150330

Hom.:

Cov.:

AF XY:

0.00162

AC XY:

119

AN XY:

73236

show subpopulations

Gnomad4 AFR

AF:

0.000196

Gnomad4 AMR

AF:

0.000668

Gnomad4 ASJ

AF:

0.000290

Gnomad4 EAS

AF:

0.00804

Gnomad4 SAS

AF:

0.0128

Gnomad4 FIN

AF:

0.000290

Gnomad4 NFE

AF:

0.00136

Gnomad4 OTH

AF:

0.00144

Alfa

AF:

0.00144

Hom.:

Bravo

AF:

0.00108

Asia WGS

AF:

0.00606

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 20, 2018	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2022	LOXHD1: BS1, BS2 -

Autosomal recessive nonsyndromic hearing loss 77

Uncertain:1Benign:1

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Dec 10, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	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. -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jun 18, 2015

p.Asn1971Asn in exon 38 of LOXHD1: This variant is not expected to have clinical significance because it has been identified in 1.2% (98/7914) of South Asian ch romosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute. org; dbSNP rs146200756). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.37

CADD

Benign

0.98

DANN

Benign

0.80

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.28

Details are displayed if max score is > 0.2

DS_AL_spliceai

0.28

Position offset: 49

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over