18-46601323-C-T

Position:

• chr18-46601323-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.1028G>A​(p.Arg343His) variant causes a missense change. The variant allele was found at a frequency of 0.00137 in 1,551,656 control chromosomes in the GnomAD database, including 27 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 0.0074 (15 hom., cov: 32)
  • Exomes 𝑓: 0.00072 (12 hom.)
• Consequence: LOXHD1 NM_001384474.1 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:5
• Conservation: PhyloP100: 5.97

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]

LOXHD1 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008596808).
• BP6: Variant 18-46601323-C-T is Benign according to our data. Variant chr18-46601323-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 178403.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=1, Benign=2}.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00739 (1125/152244) while in subpopulation AFR AF= 0.026 (1078/41532). AF 95% confidence interval is 0.0247. There are 15 homozygotes in gnomad4. There are 529 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 15 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LOXHD1	NM_001384474.1	c.1028G>A	p.Arg343His	missense_variant	8/41	ENST00000642948.1	NP_001371403.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LOXHD1	ENST00000642948.1	c.1028G>A	p.Arg343His	missense_variant	8/41		NM_001384474.1	ENSP00000496347.1
LOXHD1	ENST00000536736.5	c.1028G>A	p.Arg343His	missense_variant	8/40	5		ENSP00000444586.1
LOXHD1	ENST00000441551.6	c.1028G>A	p.Arg343His	missense_variant	8/39	5		ENSP00000387621.2
LOXHD1	ENST00000335730.6	n.341G>A		non_coding_transcript_exon_variant	1/27	2

Frequencies

GnomAD3 genomes AF: 0.00739 AC: 1124 AN: 152128 Hom.: 16 Cov.: 32

Gnomad AFR AF: 0.0260

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00177

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00621

GnomAD3 exomes AF: 0.00171 AC: 271 AN: 158432 Hom.: 5 AF XY: 0.00126 AC XY: 105 AN XY: 83454

Gnomad AFR exome AF: 0.0274

Gnomad AMR exome AF: 0.00105

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: 0.0000656

Gnomad OTH exome AF: 0.000671

GnomAD4 exome AF: 0.000715 AC: 1001 AN: 1399412 Hom.: 12 Cov.: 32 AF XY: 0.000601 AC XY: 415 AN XY: 690210

Gnomad4 AFR exome AF: 0.0258

Gnomad4 AMR exome AF: 0.000952

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000280

Gnomad4 SAS exome AF: 0.0000252

Gnomad4 FIN exome AF: 0.0000203

Gnomad4 NFE exome AF: 0.0000500

Gnomad4 OTH exome AF: 0.00147

GnomAD4 genome AF: 0.00739 AC: 1125 AN: 152244 Hom.: 15 Cov.: 32 AF XY: 0.00711 AC XY: 529 AN XY: 74432

Gnomad4 AFR AF: 0.0260

Gnomad4 AMR AF: 0.00177

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000882

Gnomad4 OTH AF: 0.00616

Alfa AF: 0.00245 Hom.: 1

Bravo AF: 0.00844

ESP6500AA AF: 0.0195 AC: 27

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00262 AC: 67

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Autosomal recessive nonsyndromic hearing loss 77 Uncertain:1 Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 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.	Dec 16, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	Counsyl	Jun 13, 2017	- -

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 12, 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	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Sep 09, 2014	Arg343His in Exon 08 of LOXHD1: This variant is not expected to have clinical si gnificance because it has been identified in 2.0% (27/1384) of African American chromosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/ EVS). -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.25
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Benign	0.26	.;.;T
Eigen	Uncertain	0.65
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.93	D;D;D
MetaRNN	Benign	0.0086	T;T;T
MetaSVM	Benign	-0.54	T
PrimateAI	Benign	0.48	T
PROVEAN	Uncertain	-2.9	D;.;.
REVEL	Uncertain	0.36
Sift	Benign	0.079	T;.;.
Sift4G	Uncertain	0.041	D;.;D
Polyphen		1.0	D;.;.
Vest4		0.36
MVP		0.20
ClinPred		0.014	T
GERP RS		5.6
Varity_R		0.11
gMVP		0.32

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: rs183531840; hg19: chr18-44181286; COSMIC: COSV59667425;