rs727504804

Positions:

• chr18-46542849-G-A
• chr18-46542849-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001384474.1(LOXHD1):​c.3626C>T​(p.Thr1209Ile) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: LOXHD1 NM_001384474.1 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 4.69

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.12673882).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LOXHD1	NM_001384474.1	c.3626C>T	p.Thr1209Ile	missense_variant	24/41	ENST00000642948.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LOXHD1	ENST00000642948.1	c.3626C>T	p.Thr1209Ile	missense_variant	24/41		NM_001384474.1	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Oct 18, 2013

Variant classified as Uncertain Significance - Favor Benign. The Thr1209Ile vari ant in LOXHD1 has not been reported in individuals with hearing loss or in large population studies. The threonine (Thr) at position 1209 is not fully conserved across species with several species including mammals (opossum and wallaby) hav ing an isoleucine (Ile) at this position. In addition, computational analyses (b iochemical amino acid properties, AlignGVGD, PolyPhen2, and SIFT) suggest that t he Thr1209Ile variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity. In summary, the clinical significa nce of this variant cannot be determined with certainty; however based upon the conservation and computational data, we would lean towards a more likely benign role. -

Autosomal recessive nonsyndromic hearing loss 77 Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Natera, Inc.

Feb 26, 2020

- -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Dec 21, 2021

This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 1209 of the LOXHD1 protein (p.Thr1209Ile). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with LOXHD1-related conditions. ClinVar contains an entry for this variant (Variation ID: 179341). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The isoleucine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	15
DANN	Benign	0.92
Eigen	Benign	-0.33
Eigen_PC	Benign	-0.075
FATHMM_MKL	Benign	0.045	N
LIST_S2	Benign	0.85	D;T;T;T;T;T
M_CAP	Benign	0.0098	T
MetaRNN	Benign	0.13	T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	0.67	N;N;N;N;N;N;N
PrimateAI	Benign	0.42	T
Sift4G	Benign	0.85	T;T;T;T;.;T
Polyphen		0.11	.;.;.;B;.;.
Vest4		0.098
MutPred		0.45		.;.;.;Loss of disorder (P = 0.0221);Loss of disorder (P = 0.0221);.;
MVP		0.23
ClinPred		0.46	T
GERP RS		3.8
Varity_R		0.084
gMVP		0.44

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: rs727504804; hg19: chr18-44122812; COSMIC: COSV56067247; COSMIC: COSV56067247;