rs200260213

Positions:

• chr18-46559498-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001384474.1(LOXHD1):​c.3166G>A​(p.Glu1056Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000825 in 1,551,880 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. E1056E) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00012 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000078 (0 hom.)
• Consequence: LOXHD1 NM_001384474.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2
• Conservation: PhyloP100: 7.87

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.40628457).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LOXHD1	NM_001384474.1	c.3166G>A	p.Glu1056Lys	missense_variant	20/41	ENST00000642948.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LOXHD1	ENST00000642948.1	c.3166G>A	p.Glu1056Lys	missense_variant	20/41		NM_001384474.1	P1
LOXHD1	ENST00000536736.5	c.3166G>A	p.Glu1056Lys	missense_variant	20/40	5
LOXHD1	ENST00000441551.6	c.2599-2009G>A		intron_variant		5
LOXHD1	ENST00000335730.6	n.2479G>A		non_coding_transcript_exon_variant	13/27	2

Frequencies

GnomAD3 genomes AF: 0.000125 AC: 19 AN: 152180 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000217

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: 0.000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000564 AC: 9 AN: 159554 Hom.: 0 AF XY: 0.0000477 AC XY: 4 AN XY: 83878

Gnomad AFR exome AF: 0.000113

Gnomad AMR exome AF: 0.0000404

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000113

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000779 AC: 109 AN: 1399700 Hom.: 0 Cov.: 33 AF XY: 0.0000869 AC XY: 60 AN XY: 690356

Gnomad4 AFR exome AF: 0.0000949

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: 0.0000908

Gnomad4 OTH exome AF: 0.0000172

GnomAD4 genome AF: 0.000125 AC: 19 AN: 152180 Hom.: 0 Cov.: 32 AF XY: 0.000108 AC XY: 8 AN XY: 74324

Gnomad4 AFR AF: 0.000217

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: 0.000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000772 Hom.: 0

Bravo AF: 0.0000945

ESP6500AA AF: 0.000723 AC: 1

ESP6500EA AF: 0.000314 AC: 1

ExAC AF: 0.0000379 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Dec 15, 2017

The p.Glu1056Lys variant in LOXHD1 has now been identified by our laboratory in 2 individuals with hearing loss, neither of whom had a second LOXHD1 variant. Th is variant has been identified in 6/73530 (0.008%) European chromosomes by the G enome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs20 0260213). Although this variant has been seen in the general population, its fre quency is not high enough to rule out a pathogenic role. Computational predictio n tools and conservation analysis suggest that the p.Glu1056Lys variant may impa ct the protein, though this information is not predictive enough to determine pa thogenicity. In summary, the clinical significance of the p.Glu1056Lys variant i s uncertain. ACMG/AMP Criteria applied: PP3. -

Autosomal recessive nonsyndromic hearing loss 77 Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Natera, Inc.

Oct 28, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Uncertain	0.015	T
BayesDel_noAF	Uncertain	-0.010
CADD	Uncertain	25
DANN	Pathogenic	1.0
Eigen	Uncertain	0.33
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.77	T;T
M_CAP	Benign	0.033	D
MetaRNN	Benign	0.41	T;T
MetaSVM	Benign	-0.59	T
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.70	T
PROVEAN	Uncertain	-3.0	D;.
REVEL	Uncertain	0.38
Sift	Benign	0.033	D;.
Sift4G	Uncertain	0.014	D;.
Polyphen		0.96	D;.
Vest4		0.72
MVP		0.26
ClinPred		0.42	T
GERP RS		5.3
gMVP		0.58

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs200260213; hg19: chr18-44139461; COSMIC: COSV100190363; COSMIC: COSV100190363;