rs759237437

Positions:

• chr18-46560252-C-CGAGGACTCCTCTGATGAG

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP3 BP6 BS2

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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:3
• Conservation: PhyloP100: 1.41

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 (HGNC:):

ACMG classification

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/exons	MANE	Protein	UniProt
LOXHD1	NM_001384474.1	c.2874_2891dupCTCATCAGAGGAGTCCTC	p.Ser964_Ser965insSerSerGluGluSerSer	disruptive_inframe_insertion	19/41	ENST00000642948.1	NP_001371403.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LOXHD1	ENST00000642948.1	c.2874_2891dupCTCATCAGAGGAGTCCTC	p.Ser964_Ser965insSerSerGluGluSerSer	disruptive_inframe_insertion	19/41		NM_001384474.1	ENSP00000496347.1
LOXHD1	ENST00000536736.5	c.2874_2891dupCTCATCAGAGGAGTCCTC	p.Ser964_Ser965insSerSerGluGluSerSer	disruptive_inframe_insertion	19/40	5		ENSP00000444586.1
LOXHD1	ENST00000441551.6	c.2599-2781_2599-2764dupCTCATCAGAGGAGTCCTC		intron_variant		5		ENSP00000387621.2
LOXHD1	ENST00000335730.6	n.2187_2204dupCTCATCAGAGGAGTCCTC		non_coding_transcript_exon_variant	12/27	2

Frequencies

GnomAD3 genomes AF: 0.00108 AC: 164 AN: 152154 Hom.: 0 Cov.: 32

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.: 0 AF XY: 0.00107 AC XY: 89 AN XY: 83500

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.: 3 Cov.: 37 AF XY: 0.00169 AC XY: 1166 AN XY: 690114

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.: 0 Cov.: 32 AF XY: 0.000954 AC XY: 71 AN XY: 74452

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.: 0

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

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

Uncertain significance, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Jul 01, 2018	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. -
Likely benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -

not provided Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 01, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 28, 2024	- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jan 17, 2019

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

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs759237437; hg19: chr18-44140215;