rs765944082

Positions:

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP3BP6

The NM_001384474.1(LOXHD1):c.2925_2933del(p.Glu976_Glu978del) variant causes a inframe deletion change. The variant allele was found at a frequency of 0.0000458 in 1,551,784 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000048 ( 0 hom. )

Consequence

LOXHD1
NM_001384474.1 inframe_deletion

Scores

Not classified

Clinical Significance

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

Conservation

PhyloP100: 6.64

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 Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP3

Nonframeshift variant in repetitive region in NM_001384474.1

BP6

Variant 18-46560210-CTCCTCCTCT-C is Benign according to our data. Variant chr18-46560210-CTCCTCCTCT-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 505089.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LOXHD1	NM_001384474.1 linkuse as main transcript	c.2925_2933del	p.Glu976_Glu978del	inframe_deletion	19/41	ENST00000642948.1	NP_001371403.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LOXHD1	ENST00000642948.1 linkuse as main transcript	c.2925_2933del	p.Glu976_Glu978del	inframe_deletion	19/41		NM_001384474.1	ENSP00000496347	P1
LOXHD1	ENST00000536736.5 linkuse as main transcript	c.2925_2933del	p.Glu976_Glu978del	inframe_deletion	19/40	5		ENSP00000444586
LOXHD1	ENST00000441551.6 linkuse as main transcript	c.2599-2730_2599-2722del		intron_variant		5		ENSP00000387621		Q8IVV2-1
LOXHD1	ENST00000335730.6 linkuse as main transcript	n.2238_2246del		non_coding_transcript_exon_variant	12/27	2

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152180

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.0000566

AC:

AN:

158876

Hom.:

AF XY:

0.0000837

AC XY:

AN XY:

83626

show subpopulations

Gnomad AFR exome

AF:

0.000114

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000878

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000815

Gnomad OTH exome

AF:

0.000223

GnomAD4 exome

AF:

0.0000479

AC:

AN:

1399604

Hom.:

AF XY:

0.0000594

AC XY:

AN XY:

690300

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000280

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000631

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000500

Gnomad4 OTH exome

AF:

0.0000861

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152180

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74332

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.000478

Alfa

AF:

0.0000434

Hom.:

Bravo

AF:

0.0000378

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Sep 22, 2017

Variant classified as Uncertain Significance - Favor Benign. The p.Glu976_Glu978 del variant in LOXHD1 has now been identified by our laboratory in the heterozyg ous state in 2 individuals with hearing loss, neither of whom had a variant affe cting the other copy of the LOXHD1 gene. This variant is located within a polygl utamic acid tract that consists of 8 glutamic acid (Glu) residues in the human r eference genome, and results in an in-frame deletion of 3 glutamic acids (Glu) r esidues. This variant has been identified in 7/73148 European chromosomes and a similar variant resulting the same amino acid change has been identified in 48/2 2822 (0.2%) of South Asian chromosomes including 1 homozygote by the Genome Aggr egation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs765944082 an d rs753461629). The variant is not predicted to alter the reading frame of the p rotein and the polyglutamic acid tract region where the variant occurs is poorly conserved across species, suggesting that the variant may be tolerated; however , this information is not sufficient to rule out pathogenicity. In summary, whil e the clinical significance of the p.Glu976_Glu978del variant is uncertain, avai lable data suggest that it is more likely to be benign. -

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 13, 2018

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

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