18-46509818-G-A

Position:

• chr18-46509818-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.5400-3C>T variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000418 in 1,541,086 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00068 (2 hom., cov: 32)
  • Exomes 𝑓: 0.00039 (8 hom.)
• Consequence: LOXHD1 NM_001384474.1 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.0001079
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:7
• Conservation: PhyloP100: 2.84

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 (BayesDel_noAF=-0.49).
• BP6: Variant 18-46509818-G-A is Benign according to our data. Variant chr18-46509818-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 163897.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Benign=4, Likely_benign=2}.
• BS1: Variant frequency is greater than expected in population amr. gnomad4_exome allele frequency = 0.00039 (541/1388808) while in subpopulation AMR AF= 0.0116 (413/35478). AF 95% confidence interval is 0.0107. There are 8 homozygotes in gnomad4_exome. There are 226 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LOXHD1	NM_001384474.1	c.5400-3C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000642948.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LOXHD1	ENST00000642948.1	c.5400-3C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant			NM_001384474.1	P1

Frequencies

GnomAD3 genomes AF: 0.000677 AC: 103 AN: 152160 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00425

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000578

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.000565

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.000957

GnomAD3 exomes AF: 0.00217 AC: 343 AN: 158194 Hom.: 6 AF XY: 0.00164 AC XY: 137 AN XY: 83364

Gnomad AFR exome AF: 0.000231

Gnomad AMR exome AF: 0.0128

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000219

Gnomad FIN exome AF: 0.000237

Gnomad NFE exome AF: 0.0000822

Gnomad OTH exome AF: 0.00202

GnomAD4 exome AF: 0.000390 AC: 541 AN: 1388808 Hom.: 8 Cov.: 31 AF XY: 0.000330 AC XY: 226 AN XY: 685452

Gnomad4 AFR exome AF: 0.000352

Gnomad4 AMR exome AF: 0.0116

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000759

Gnomad4 FIN exome AF: 0.000305

Gnomad4 NFE exome AF: 0.0000690

Gnomad4 OTH exome AF: 0.000350

GnomAD4 genome AF: 0.000676 AC: 103 AN: 152278 Hom.: 2 Cov.: 32 AF XY: 0.000725 AC XY: 54 AN XY: 74458

Gnomad4 AFR AF: 0.000481

Gnomad4 AMR AF: 0.00425

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000580

Gnomad4 SAS AF: 0.000416

Gnomad4 FIN AF: 0.000565

Gnomad4 NFE AF: 0.0000735

Gnomad4 OTH AF: 0.000947

Alfa AF: 0.000184 Hom.: 0

Bravo AF: 0.00149

Asia WGS AF: 0.00144 AC: 5 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:7

Revision: criteria provided, conflicting classifications

Submissions by phenotype

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

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.	Oct 21, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 06, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Counsyl	Nov 03, 2017	- -

not provided Uncertain:1 Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 15, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Sep 12, 2018	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 09, 2017	c.5214-3C>T variant in intron 33 of LOXHD1: This variant is not expected to have clinical significance because it does not cause a divergence from the splicing consensus sequence, and computational tools do not suggest an impact to splicing . It has been identified in 1% (310/24788) of Latino chromosomes including 4 ho mozygotes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitu te.org; dbSNP rs528236655). -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 30, 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.49
CADD	Benign	9.0
DANN	Benign	0.58

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00011
dbscSNV1_RF	Benign	0.036
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: rs528236655; hg19: chr18-44089781; COSMIC: COSV56068624;