rs146200756

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP6BS1BS2

The NM_001384474.1(LOXHD1):c.6099C>T(p.Asn2033Asn) 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

Publications

3 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

LOXHD1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 VariationId is 178392.

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 the male GnomAd4 subpopulation. Median coverage is 30. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 4 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LOXHD1	NM_001384474.1 link	c.6099C>T	p.Asn2033Asn	synonymous_variant	Exon 39 of 41	ENST00000642948.1	NP_001371403.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LOXHD1	ENST00000642948.1 link	c.6099C>T	p.Asn2033Asn	synonymous_variant	Exon 39 of 41		NM_001384474.1	ENSP00000496347.1

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

GnomAD2 exomes

AF:

0.00342

AC:

540

AN:

158032

AF XY:

0.00407

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 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

African (AFR)

AF:

0.000253

AC:

AN:

31598

American (AMR)

AF:

0.000840

AC:

AN:

35696

Ashkenazi Jewish (ASJ)

AF:

0.000596

AC:

AN:

25170

East Asian (EAS)

AF:

0.00521

AC:

186

AN:

35734

South Asian (SAS)

AF:

0.0113

AC:

897

AN:

79182

European-Finnish (FIN)

AF:

0.000142

AC:

AN:

49464

Middle Eastern (MID)

AF:

0.00930

AC:

AN:

5696

European-Non Finnish (NFE)

AF:

0.00126

AC:

1362

AN:

1078790

Other (OTH)

AF:

0.00255

AC:

148

AN:

58106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.461

Heterozygous variant carriers

141

283

424

566

707

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

108

162

216

270

<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:

0.00144

AC:

217

AN:

150330

Hom.:

Cov.:

AF XY:

0.00162

AC XY:

119

AN XY:

73236

show subpopulations

African (AFR)

AF:

0.000196

AC:

AN:

40788

American (AMR)

AF:

0.000668

AC:

AN:

14962

Ashkenazi Jewish (ASJ)

AF:

0.000290

AC:

AN:

3450

East Asian (EAS)

AF:

0.00804

AC:

AN:

5100

South Asian (SAS)

AF:

0.0128

AC:

AN:

4626

European-Finnish (FIN)

AF:

0.000290

AC:

AN:

10338

Middle Eastern (MID)

AF:

0.00

AC:

AN:

288

European-Non Finnish (NFE)

AF:

0.00136

AC:

AN:

67782

Other (OTH)

AF:

0.00144

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<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:

0.00144

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

Nov 27, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 20, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

LOXHD1: BS1, BS2 -

Autosomal recessive nonsyndromic hearing loss 77

Uncertain:1Benign:1

Jan 13, 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. -

Dec 10, 2019

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not specified

Benign:1

Jun 18, 2015

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

(source)

DANN

Benign

0.80

PhyloP100

-0.14

Mutation Taster

=98/2

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over