rs112618498

Positions:

• chr18-46639670-G-A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001384474.1(LOXHD1):​c.457C>T​(p.Arg153Cys) variant causes a missense change. The variant allele was found at a frequency of 0.000755 in 1,551,722 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0038 (5 hom., cov: 32)
  • Exomes 𝑓: 0.00042 (3 hom.)
• Consequence: LOXHD1 NM_001384474.1 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:5
• Conservation: PhyloP100: 4.71

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 Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.007599801).
• BP6: Variant 18-46639670-G-A is Benign according to our data. Variant chr18-46639670-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 47938.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Benign=3, Uncertain_significance=1}.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00383 (584/152314) while in subpopulation AFR AF= 0.0136 (564/41568). AF 95% confidence interval is 0.0126. There are 5 homozygotes in gnomad4. There are 258 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LOXHD1	NM_001384474.1	c.457C>T	p.Arg153Cys	missense_variant	4/41	ENST00000642948.1	NP_001371403.1
LOXHD1	NM_144612.7	c.457C>T	p.Arg153Cys	missense_variant	4/40		NP_653213.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LOXHD1	ENST00000642948.1	c.457C>T	p.Arg153Cys	missense_variant	4/41		NM_001384474.1	ENSP00000496347	P1
LOXHD1	ENST00000536736.5	c.457C>T	p.Arg153Cys	missense_variant	4/40	5		ENSP00000444586
LOXHD1	ENST00000441551.6	c.457C>T	p.Arg153Cys	missense_variant	4/39	5		ENSP00000387621

Frequencies

GnomAD3 genomes AF: 0.00382 AC: 582 AN: 152196 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.0136

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000720

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.000862 AC: 135 AN: 156568 Hom.: 0 AF XY: 0.000566 AC XY: 47 AN XY: 82986

Gnomad AFR exome AF: 0.0146

Gnomad AMR exome AF: 0.000486

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000439

Gnomad FIN exome AF: 0.0000595

Gnomad NFE exome AF: 0.0000660

Gnomad OTH exome AF: 0.000228

GnomAD4 exome AF: 0.000419 AC: 587 AN: 1399408 Hom.: 3 Cov.: 31 AF XY: 0.000354 AC XY: 244 AN XY: 690220

Gnomad4 AFR exome AF: 0.0150

Gnomad4 AMR exome AF: 0.000336

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000252

Gnomad4 FIN exome AF: 0.000101

Gnomad4 NFE exome AF: 0.0000287

Gnomad4 OTH exome AF: 0.00107

GnomAD4 genome AF: 0.00383 AC: 584 AN: 152314 Hom.: 5 Cov.: 32 AF XY: 0.00346 AC XY: 258 AN XY: 74460

Gnomad4 AFR AF: 0.0136

Gnomad4 AMR AF: 0.000719

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.0000942

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.00223 Hom.: 0

Bravo AF: 0.00445

ESP6500AA AF: 0.0130 AC: 18

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00167 AC: 43

Asia WGS AF: 0.00173 AC: 6 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 09, 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. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2023	LOXHD1: BP4, BS1, BS2 -

Autosomal recessive nonsyndromic hearing loss 77 Uncertain:1 Benign:1

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Nov 11, 2019	- -
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. -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Dec 10, 2012

Arg153Cys in exon 4 of LOXHD1: This variant is not expected to have clinical sig nificance because it has been identified in 1.3% (18/1384) of African American c hromosomes from a broad population by the NHLBI Exome Sequencing Project (http:/ /evs.gs.washington.edu/EVS/; dbSNP rs112618498) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.25
CADD	Pathogenic	27
DANN	Uncertain	0.99
Eigen	Uncertain	0.47
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.89	D;D;D
MetaRNN	Benign	0.0076	T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	D;D
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-1.7	N;.;.
REVEL	Benign	0.18
Sift	Uncertain	0.020	D;.;.
Sift4G	Uncertain	0.013	D;.;D
Polyphen		1.0	D;.;.
Vest4		0.39
MVP		0.28
ClinPred		0.032	T
GERP RS		5.8
Varity_R		0.16
gMVP		0.58

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs112618498; hg19: chr18-44219633;