rs187587197

Positions:

• chr18-46529181-C-T

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.4526G>A​(p.Gly1509Glu) variant causes a missense change. The variant allele was found at a frequency of 0.0063 in 1,551,526 control chromosomes in the GnomAD database, including 107 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 0.0070 (19 hom., cov: 32)
  • Exomes 𝑓: 0.0062 (88 hom.)
• Consequence: LOXHD1 NM_001384474.1 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:9
• Conservation: PhyloP100: 6.07

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=0.008006483).
• BP6: Variant 18-46529181-C-T is Benign according to our data. Variant chr18-46529181-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 178612.We mark this variant Likely_benign, oryginal submissions are: {Benign=7, Uncertain_significance=1, Likely_benign=1}. Variant chr18-46529181-C-T is described in Lovd as [Likely_benign]. Variant chr18-46529181-C-T is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00697 (1061/152134) while in subpopulation NFE AF= 0.0056 (381/68006). AF 95% confidence interval is 0.00514. There are 19 homozygotes in gnomad4. There are 645 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 19 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LOXHD1	NM_001384474.1	c.4526G>A	p.Gly1509Glu	missense_variant	29/41	ENST00000642948.1	NP_001371403.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LOXHD1	ENST00000642948.1	c.4526G>A	p.Gly1509Glu	missense_variant	29/41		NM_001384474.1	ENSP00000496347	P1

Frequencies

GnomAD3 genomes AF: 0.00698 AC: 1061 AN: 152016 Hom.: 19 Cov.: 32

Gnomad AFR AF: 0.000967

Gnomad AMI AF: 0.0219

Gnomad AMR AF: 0.000590

Gnomad ASJ AF: 0.00259

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.0560

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00560

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.00783 AC: 1242 AN: 158560 Hom.: 27 AF XY: 0.00735 AC XY: 614 AN XY: 83516

Gnomad AFR exome AF: 0.00137

Gnomad AMR exome AF: 0.000647

Gnomad ASJ exome AF: 0.00176

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000702

Gnomad FIN exome AF: 0.0519

Gnomad NFE exome AF: 0.00460

Gnomad OTH exome AF: 0.00514

GnomAD4 exome AF: 0.00622 AC: 8711 AN: 1399392 Hom.: 88 Cov.: 32 AF XY: 0.00609 AC XY: 4202 AN XY: 690196

Gnomad4 AFR exome AF: 0.000791

Gnomad4 AMR exome AF: 0.000728

Gnomad4 ASJ exome AF: 0.00171

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000808

Gnomad4 FIN exome AF: 0.0528

Gnomad4 NFE exome AF: 0.00529

Gnomad4 OTH exome AF: 0.00421

GnomAD4 genome AF: 0.00697 AC: 1061 AN: 152134 Hom.: 19 Cov.: 32 AF XY: 0.00867 AC XY: 645 AN XY: 74354

Gnomad4 AFR AF: 0.000964

Gnomad4 AMR AF: 0.000589

Gnomad4 ASJ AF: 0.00259

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00104

Gnomad4 FIN AF: 0.0560

Gnomad4 NFE AF: 0.00560

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.00471 Hom.: 7

Bravo AF: 0.00271

TwinsUK AF: 0.00405 AC: 15

ALSPAC AF: 0.00545 AC: 21

ESP6500AA AF: 0.00145 AC: 2

ESP6500EA AF: 0.00440 AC: 14

ExAC AF: 0.00569 AC: 152

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:9

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Autosomal recessive nonsyndromic hearing loss 77 Uncertain:1 Benign:3

Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Likely benign, no assertion criteria provided	clinical testing	Natera, Inc.	Jan 08, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	Counsyl	Mar 16, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

not provided Benign:4

Benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Mar 17, 2017	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	LOXHD1: BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 26, 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. -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 12, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 07, 2016	p.Gly1509Glu in exon 29 of LOXHD1: This variant is not expected to have clinical significance because it has been identified in 5% (80/1614) of Finnish chromoso mes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; d bSNP rs187587197). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.49
BayesDel_addAF	Benign	-0.084	T
BayesDel_noAF	Uncertain	0.12
CADD	Pathogenic	27
DANN	Uncertain	0.98
DEOGEN2	Benign	0.19	.;.;T;.;.;.
Eigen	Pathogenic	0.88
Eigen_PC	Pathogenic	0.80
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	D;D;D;D;D;D
MetaRNN	Benign	0.0080	T;T;T;T;T;T
MetaSVM	Benign	-0.39	T
MutationTaster	Benign	1.0	D;D;D;D;D;D;D
PrimateAI	Uncertain	0.67	T
PROVEAN	Pathogenic	-6.1	.;D;.;D;.;.
REVEL	Pathogenic	0.82
Sift	Uncertain	0.0050	.;D;.;D;.;.
Sift4G	Uncertain	0.0070	D;D;D;D;.;D
Polyphen		1.0	.;.;.;D;.;.
Vest4		0.74
MVP		0.22
ClinPred		0.034	T
GERP RS		5.1
Varity_R		0.52
gMVP		0.61

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: rs187587197; hg19: chr18-44109144;