rs759237437

Variant names:

Variant summary

Our verdict is Likely benign. Variant got -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. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

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

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:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -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 id is 228821.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=2}.

BS2

High Homozygotes in GnomAdExome4 at 3 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	UniProt
LOXHD1	ENST00000642948.1 link	c.2874_2891dupCTCATCAGAGGAGTCCTC	p.Ser964_Ser965insSerSerGluGluSerSer	disruptive_inframe_insertion	Exon 19 of 41		NM_001384474.1	ENSP00000496347.1	A0A2R8Y7K4
LOXHD1	ENST00000536736.5 link	c.2874_2891dupCTCATCAGAGGAGTCCTC	p.Ser964_Ser965insSerSerGluGluSerSer	disruptive_inframe_insertion	Exon 19 of 40	5		ENSP00000444586.1	F5GZB4
LOXHD1	ENST00000441551.6 link	c.2599-2781_2599-2764dupCTCATCAGAGGAGTCCTC		intron_variant	Intron 18 of 38	5		ENSP00000387621.2	Q8IVV2-1
LOXHD1	ENST00000335730.6 link	n.2187_2204dupCTCATCAGAGGAGTCCTC		non_coding_transcript_exon_variant	Exon 12 of 27	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

GnomAD3 exomes

AF:

0.00113

AC:

179

AN:

158546

Hom.:

AF XY:

0.00107

AC XY:

AN XY:

83500

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 SAS exome

AF:

0.0000439

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

Gnomad4 AFR exome

AF:

0.000222

Gnomad4 AMR exome

AF:

0.00162

Gnomad4 ASJ exome

AF:

0.000238

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000126

Gnomad4 FIN exome

AF:

0.00111

Gnomad4 NFE exome

AF:

0.00208

Gnomad4 OTH exome

AF:

0.000810

GnomAD4 genome

AF:

0.00108

AC:

164

AN:

152272

Hom.:

Cov.:

AF XY:

0.000954

AC XY:

AN XY:

74452

show subpopulations

Gnomad4 AFR

AF:

0.000265

Gnomad4 AMR

AF:

0.00274

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000659

Gnomad4 NFE

AF:

0.00141

Gnomad4 OTH

AF:

0.00331

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

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. -

Sep 16, 2020

Natera, Inc.

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

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

Splicing

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