rs759237437

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP3BP6BS2

The NM_001384474.1(LOXHD1):c.2874_2891dupCTCATCAGAGGAGTCCTC(p.Ser964_Ser965insSerSerGluGluSerSer) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00166 in 1,551,366 control chromosomes in the GnomAD database, including 3 homozygotes. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. S964S) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0011 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0017 ( 3 hom. )

Consequence

LOXHD1
NM_001384474.1 disruptive_inframe_insertion

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:3

Conservation

PhyloP100: 1.41

Publications

2 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: Likely_benign. The variant received -6 ACMG points.

BP3

Nonframeshift variant in repetitive region in NM_001384474.1

BP6

Variant 18-46560252-C-CGAGGACTCCTCTGATGAG is Benign according to our data. Variant chr18-46560252-C-CGAGGACTCCTCTGATGAG is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 228821.

BS2

High Homozygotes in GnomAdExome4 at 3 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LOXHD1	NM_001384474.1 link	c.2874_2891dupCTCATCAGAGGAGTCCTC	p.Ser964_Ser965insSerSerGluGluSerSer	disruptive_inframe_insertion	Exon 19 of 41	ENST00000642948.1	NP_001371403.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
LOXHD1	ENST00000642948.1 link	c.2874_2891dupCTCATCAGAGGAGTCCTC	p.Ser964_Ser965insSerSerGluGluSerSer	disruptive_inframe_insertion	Exon 19 of 41		NM_001384474.1	ENSP00000496347.1
LOXHD1	ENST00000536736.5 link	c.2874_2891dupCTCATCAGAGGAGTCCTC	p.Ser964_Ser965insSerSerGluGluSerSer	disruptive_inframe_insertion	Exon 19 of 40	5		ENSP00000444586.1
LOXHD1	ENST00000335730.6 link	n.2187_2204dupCTCATCAGAGGAGTCCTC		non_coding_transcript_exon_variant	Exon 12 of 27	2
LOXHD1	ENST00000441551.6 link	c.2599-2781_2599-2764dupCTCATCAGAGGAGTCCTC		intron_variant	Intron 18 of 38	5		ENSP00000387621.2

Frequencies

GnomAD3 genomes

AF:

0.00108

AC:

164

AN:

152154

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000265

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00275

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000659

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00141

Gnomad OTH

AF:

0.00335

GnomAD2 exomes

AF:

0.00113

AC:

179

AN:

158546

AF XY:

0.00107

show subpopulations

Gnomad AFR exome

AF:

0.000113

Gnomad AMR exome

AF:

0.00141

Gnomad ASJ exome

AF:

0.000353

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000721

Gnomad NFE exome

AF:

0.00199

Gnomad OTH exome

AF:

0.00111

GnomAD4 exome

AF:

0.00173

AC:

2414

AN:

1399094

Hom.:

Cov.:

AF XY:

0.00169

AC XY:

1166

AN XY:

690114

show subpopulations

African (AFR)

AF:

0.000222

AC:

AN:

31576

American (AMR)

AF:

0.00162

AC:

AN:

35704

Ashkenazi Jewish (ASJ)

AF:

0.000238

AC:

AN:

25180

East Asian (EAS)

AF:

0.00

AC:

AN:

35742

South Asian (SAS)

AF:

0.0000126

AC:

AN:

79226

European-Finnish (FIN)

AF:

0.00111

AC:

AN:

49404

Middle Eastern (MID)

AF:

0.000175

AC:

AN:

5700

European-Non Finnish (NFE)

AF:

0.00208

AC:

2239

AN:

1078506

Other (OTH)

AF:

0.000810

AC:

AN:

58056

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

Heterozygous variant carriers

120

241

361

482

602

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

188

282

376

470

<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:

0.00108

AC:

164

AN:

152272

Hom.:

Cov.:

AF XY:

0.000954

AC XY:

AN XY:

74452

show subpopulations

African (AFR)

AF:

0.000265

AC:

AN:

41566

American (AMR)

AF:

0.00274

AC:

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.000288

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5162

South Asian (SAS)

AF:

0.00

AC:

AN:

4816

European-Finnish (FIN)

AF:

0.000659

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00141

AC:

AN:

68016

Other (OTH)

AF:

0.00331

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

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:

0.000735

Hom.:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Autosomal recessive nonsyndromic hearing loss 77

Uncertain:1Benign:1

Sep 16, 2020

Natera, Inc.

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Jul 01, 2018

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

A heterozygous inframe insertion variant, NM_144612.6(LOXHD1):c.2874_2891dupCTCATCAGAGGAGTCCTC, has been identified in exon 19 of 40 of the LOXHD1 gene. The variant is predicted to result in an inframe insertion of six amino acids at position 960 to 965 of the protein, NP_653213.6(LOXHD1):p.(Ser960_Ser965dup). This region has low conservation (100 vertebrates, UCSC), and the insertion is not located within a well established functional domain. This variant is present in the gnomAD database at a frequency of 0.1097% (200 heterozygotes, 0 homozygotes) and has been previously described as a VUS (ClinVar), however has not been reported in individuals with hearing loss. Based on the information available at the time of curation, this variant has been classified as VARIANT of UNCERTAIN SIGNIFICANCE (VUS) with LOW CLINICAL RELEVANCE.

not provided

Uncertain:1Benign:1

Dec 01, 2017

Eurofins Ntd Llc (ga)

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

not specified

Benign:1

Jan 17, 2019

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.2874_2891dup (p.Ser959_Ser964dup) variant in LOXHD1 is classified as likel y benign because it has been identified in 0.20% (147/76596) of European chromos omes by gnomAD (http://gnomad.broadinstitute.org) and it is an in-frame duplicat ion of 6 amino acids in a repeat region of LOXHD1 with multiple in-frame deletio ns and duplications in the general population. ACMG/AMP criteria: BS1_Supporting , BP3.

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

1.4

Mutation Taster

=66/34

polymorphism

(source)

Splicing

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