rs200763838

Variant names:

• chr18-46649234-C-T
• rs200763838
• NM_001384474.1:c.166G>A

Variant summary

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

The NM_001384474.1(LOXHD1):​c.166G>A​(p.Gly56Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000259 in 1,551,830 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00034 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00025 (1 hom.)
• Consequence: LOXHD1 NM_001384474.1 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: 7.84

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=0.19751024).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LOXHD1	NM_001384474.1	c.166G>A	p.Gly56Ser	missense_variant	Exon 2 of 41	ENST00000642948.1	NP_001371403.1
LOXHD1	NM_144612.7	c.166G>A	p.Gly56Ser	missense_variant	Exon 2 of 40		NP_653213.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LOXHD1	ENST00000642948.1	c.166G>A	p.Gly56Ser	missense_variant	Exon 2 of 41		NM_001384474.1	ENSP00000496347.1
LOXHD1	ENST00000536736.5	c.166G>A	p.Gly56Ser	missense_variant	Exon 2 of 40	5		ENSP00000444586.1
LOXHD1	ENST00000441551.6	c.166G>A	p.Gly56Ser	missense_variant	Exon 2 of 39	5		ENSP00000387621.2

Frequencies

GnomAD3 genomes AF: 0.000342 AC: 52 AN: 152142 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000579

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000393

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: 0.000309

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000279 AC: 44 AN: 157526 Hom.: 0 AF XY: 0.000240 AC XY: 20 AN XY: 83246

Gnomad AFR exome AF: 0.000616

Gnomad AMR exome AF: 0.000445

Gnomad ASJ exome AF: 0.000117

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000439

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000327

Gnomad OTH exome AF: 0.00135

GnomAD4 exome AF: 0.000250 AC: 350 AN: 1399570 Hom.: 1 Cov.: 31 AF XY: 0.000261 AC XY: 180 AN XY: 690280

Gnomad4 AFR exome AF: 0.000791

Gnomad4 AMR exome AF: 0.000448

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000252

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000245

Gnomad4 OTH exome AF: 0.000603

GnomAD4 genome AF: 0.000342 AC: 52 AN: 152260 Hom.: 0 Cov.: 33 AF XY: 0.000296 AC XY: 22 AN XY: 74430

Gnomad4 AFR AF: 0.000578

Gnomad4 AMR AF: 0.000392

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000309

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000260 Hom.: 0

Bravo AF: 0.000408

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.000723 AC: 1

ESP6500EA AF: 0.000943 AC: 3

ExAC AF: 0.000223 AC: 6

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

May 21, 2019

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Gly56Ser variant in LOXHD1 has been identified in 1 individual with hearing loss by our laboratory; however, a variant affecting the remaining copy of LOXHD1 was not identified. This variant has also been identified in 0.03% (57/188894) of total chromosomes by gnomAD (http://gnomad.broadinstitute.org). Computational prediction tools and conservation analysis suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PM2_Supporting, PP3. -

Inborn genetic diseases Uncertain:1

Sep 28, 2018

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Autosomal recessive nonsyndromic hearing loss 77 Uncertain:1

Sep 16, 2020

Natera, Inc.

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided Uncertain:1

Oct 04, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 56 of the LOXHD1 protein (p.Gly56Ser). This variant is present in population databases (rs200763838, gnomAD 0.06%). 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: 504611). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Not Available"; Align-GVGD: "Class C0"). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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	0.33
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.15
CADD	Uncertain	24
DANN	Benign	0.97
Eigen	Uncertain	0.28
Eigen_PC	Uncertain	0.29
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.92	D;D;D
M_CAP	Uncertain	0.098	D
MetaRNN	Benign	0.20	T;T;T
MetaSVM	Benign	-0.52	T
PrimateAI	Uncertain	0.69	T
PROVEAN	Uncertain	-4.3	D;.;.
REVEL	Uncertain	0.52
Sift	Uncertain	0.024	D;.;.
Sift4G	Uncertain	0.0050	D;.;D
Polyphen		1.0	D;.;.
Vest4		0.73
MVP		0.24
ClinPred		0.080	T
GERP RS		4.3
Varity_R		0.10
gMVP		0.77

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: rs200763838; hg19: chr18-44229197;