18-46642008-C-T

Position:

• chr18-46642008-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.274G>A​(p.Val92Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00111 in 1,552,360 control chromosomes in the GnomAD database, including 18 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0060 (10 hom., cov: 33)
  • Exomes 𝑓: 0.00057 (8 hom.)
• Consequence: LOXHD1 NM_001384474.1 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4
• Conservation: PhyloP100: 4.58

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=0.0056231916).
• BP6: Variant 18-46642008-C-T is Benign according to our data. Variant chr18-46642008-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 163940.We mark this variant Likely_benign, oryginal submissions are: {Benign=3, Uncertain_significance=1}.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00604 (921/152364) while in subpopulation AFR AF= 0.0211 (878/41584). AF 95% confidence interval is 0.02. There are 10 homozygotes in gnomad4. There are 416 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 10 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LOXHD1	NM_001384474.1	c.274G>A	p.Val92Ile	missense_variant	3/41	ENST00000642948.1	NP_001371403.1
LOXHD1	NM_144612.7	c.274G>A	p.Val92Ile	missense_variant	3/40		NP_653213.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LOXHD1	ENST00000642948.1	c.274G>A	p.Val92Ile	missense_variant	3/41		NM_001384474.1	ENSP00000496347	P1
LOXHD1	ENST00000536736.5	c.274G>A	p.Val92Ile	missense_variant	3/40	5		ENSP00000444586
LOXHD1	ENST00000441551.6	c.274G>A	p.Val92Ile	missense_variant	3/39	5		ENSP00000387621

Frequencies

GnomAD3 genomes AF: 0.00604 AC: 920 AN: 152246 Hom.: 9 Cov.: 33

Gnomad AFR AF: 0.0212

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00222

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: 0.0000441

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.00122 AC: 194 AN: 158712 Hom.: 3 AF XY: 0.000873 AC XY: 73 AN XY: 83626

Gnomad AFR exome AF: 0.0204

Gnomad AMR exome AF: 0.000889

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000162

Gnomad OTH exome AF: 0.000443

GnomAD4 exome AF: 0.000569 AC: 797 AN: 1399996 Hom.: 8 Cov.: 30 AF XY: 0.000511 AC XY: 353 AN XY: 690470

Gnomad4 AFR exome AF: 0.0220

Gnomad4 AMR exome AF: 0.000588

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000280

Gnomad4 SAS exome AF: 0.0000252

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000148

Gnomad4 OTH exome AF: 0.000997

GnomAD4 genome AF: 0.00604 AC: 921 AN: 152364 Hom.: 10 Cov.: 33 AF XY: 0.00558 AC XY: 416 AN XY: 74514

Gnomad4 AFR AF: 0.0211

Gnomad4 AMR AF: 0.00222

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.000871 Hom.: 2

Bravo AF: 0.00692

ESP6500AA AF: 0.0267 AC: 37

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00228 AC: 60

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

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

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. -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 06, 2018	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 31, 2016

p.Val92Ile in Exon 03 of LOXHD1: This variant is not expected to have clinical s ignificance because it has been identified in 2.2% (53/2362) of African chromoso mes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; d bSNP rs115275492). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	17
DANN	Benign	0.94
DEOGEN2	Benign	0.032	.;.;T
Eigen	Benign	-0.26
Eigen_PC	Benign	-0.21
FATHMM_MKL	Benign	0.57	D
LIST_S2	Benign	0.80	T;T;T
MetaRNN	Benign	0.0056	T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-0.50	N;.;.
REVEL	Benign	0.17
Sift	Benign	0.38	T;.;.
Sift4G	Uncertain	0.010	D;.;D
Polyphen		0.80	P;.;.
Vest4		0.16
MVP		0.12
ClinPred		0.024	T
GERP RS		3.8
Varity_R		0.050
gMVP		0.35

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: rs115275492; hg19: chr18-44221971;