chr18-46610813-T-C

Position:

• chr18-46610813-T-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001384474.1(LOXHD1):​c.722A>G​(p.Asn241Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000416 in 1,551,698 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 0.00042 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00042 (1 hom.)
• Consequence: LOXHD1 NM_001384474.1 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:8 B:1
• Conservation: PhyloP100: 7.88

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.032109827).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LOXHD1	NM_001384474.1	c.722A>G	p.Asn241Ser	missense_variant	6/41	ENST00000642948.1	NP_001371403.1
LOXHD1	NM_144612.7	c.722A>G	p.Asn241Ser	missense_variant	6/40		NP_653213.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LOXHD1	ENST00000642948.1	c.722A>G	p.Asn241Ser	missense_variant	6/41		NM_001384474.1	ENSP00000496347.1
LOXHD1	ENST00000536736.5	c.722A>G	p.Asn241Ser	missense_variant	6/40	5		ENSP00000444586.1
LOXHD1	ENST00000441551.6	c.722A>G	p.Asn241Ser	missense_variant	6/39	5		ENSP00000387621.2

Frequencies

GnomAD3 genomes AF: 0.000420 AC: 64 AN: 152208 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00183

Gnomad ASJ AF: 0.000577

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000397

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000415 AC: 65 AN: 156600 Hom.: 0 AF XY: 0.000386 AC XY: 32 AN XY: 82970

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00150

Gnomad ASJ exome AF: 0.000706

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000297

Gnomad OTH exome AF: 0.000910

GnomAD4 exome AF: 0.000415 AC: 581 AN: 1399372 Hom.: 1 Cov.: 30 AF XY: 0.000391 AC XY: 270 AN XY: 690178

Gnomad4 AFR exome AF: 0.0000317

Gnomad4 AMR exome AF: 0.00179

Gnomad4 ASJ exome AF: 0.000794

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000440

Gnomad4 OTH exome AF: 0.000345

GnomAD4 genome AF: 0.000420 AC: 64 AN: 152326 Hom.: 0 Cov.: 32 AF XY: 0.000483 AC XY: 36 AN XY: 74476

Gnomad4 AFR AF: 0.000144

Gnomad4 AMR AF: 0.00183

Gnomad4 ASJ AF: 0.000577

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000397

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000409 Hom.: 0

Bravo AF: 0.000476

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000519 AC: 2

ExAC AF: 0.000194 AC: 5

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:8 Benign:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:4

Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2023	LOXHD1: PM2 -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jul 08, 2022	This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 241 of the LOXHD1 protein (p.Asn241Ser). This variant is present in population databases (rs191697915, gnomAD 0.2%). 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: 198278). 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: "Benign"; 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 16, 2014	- -
Uncertain significance, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The LOXHD1 p.Asn241Ser variant was not identified in the literature nor was it identified in LOVD 3.0. The variant was identified in dbSNP (ID: rs191697915) and ClinVar (classified as uncertain significance by EGL Genetics and Laboratory for Molecular Medicine). The variant was identified in control databases in 73 of 187990 chromosomes at a frequency of 0.0003883 (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: Latino in 40 of 25514 chromosomes (freq: 0.001568), Other in 5 of 5484 chromosomes (freq: 0.000912), Ashkenazi Jewish in 7 of 8790 chromosomes (freq: 0.000796) and European (non-Finnish) in 21 of 76012 chromosomes (freq: 0.000276), but was not observed in the African, East Asian, European (Finnish), or South Asian populations. The p.Asn241 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and three of four in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -

Autosomal recessive nonsyndromic hearing loss 77 Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Nov 11, 2019	- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Nov 27, 2018

The p.Asn241Ser variant in LOXHD1 has been previously reported by our laboratory in 1 individual with hearing loss. It has also been identified in 0.15% (40/255 14) of Latino chromosomes by gnomAD (http://gnomad.broadinstitute.org), and has been reported in ClinVar (Variation ID 198278). Computational prediction tools a nd conservation analysis suggest that the variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summar y, the clinical significance of the p.Asn241Ser variant is uncertain. ACMG/AMP c riteria: BS1_Supporting, PP3. -

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 10, 2021

The c.722A>G (p.N241S) alteration is located in exon 6 (coding exon 6) of the LOXHD1 gene. This alteration results from a A to G substitution at nucleotide position 722, causing the asparagine (N) at amino acid position 241 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

LOXHD1-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 12, 2023

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.53
CADD	Uncertain	23
DANN	Benign	0.94
DEOGEN2	Benign	0.019	.;.;T
Eigen	Pathogenic	0.73
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.93	D;D;D
M_CAP	Benign	0.031	D
MetaRNN	Benign	0.032	T;T;T
MetaSVM	Benign	-0.81	T
PrimateAI	Uncertain	0.58	T
PROVEAN	Uncertain	-2.9	D;.;.
REVEL	Uncertain	0.35
Sift	Uncertain	0.028	D;.;.
Sift4G	Uncertain	0.0050	D;.;D
Polyphen		1.0	D;.;.
Vest4		0.57
MVP		0.17
ClinPred		0.10	T
GERP RS		5.7
Varity_R		0.19
gMVP		0.21

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: rs191697915; hg19: chr18-44190776;