rs117403100

Variant names:

• chr18-46524936-G-A
• rs117403100
• NM_001384474.1:c.4531-19C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001384474.1(LOXHD1):​c.4531-19C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0351 in 1,551,238 control chromosomes in the GnomAD database, including 1,134 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.026 (79 hom., cov: 32)
  • Exomes 𝑓: 0.036 (1055 hom.)
• Consequence: LOXHD1 NM_001384474.1 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.474
• Publications: 1 publications found

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 Gene-Disease associations (from GenCC):

• autosomal recessive nonsyndromic hearing loss 77

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, PanelApp Australia, Labcorp Genetics (formerly Invitae), Ambry Genetics
• nonsyndromic genetic hearing loss

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• hearing loss, autosomal recessive

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• Fuchs' endothelial dystrophy

  Inheritance: AD Classification: LIMITED Submitted by: Illumina

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.74).
• BP6: Variant 18-46524936-G-A is Benign according to our data. Variant chr18-46524936-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 262521.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0262 (3992/152242) while in subpopulation NFE AF = 0.0388 (2637/68000). AF 95% confidence interval is 0.0375. There are 79 homozygotes in GnomAd4. There are 1915 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 79 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LOXHD1	NM_001384474.1	c.4531-19C>T		intron_variant	Intron 29 of 40	ENST00000642948.1	NP_001371403.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LOXHD1	ENST00000642948.1	c.4531-19C>T		intron_variant	Intron 29 of 40		NM_001384474.1	ENSP00000496347.1

Frequencies

GnomAD3 genomes AF: 0.0263 AC: 3996 AN: 152126 Hom.: 80 Cov.: 32

Gnomad AFR AF: 0.00707

Gnomad AMI AF: 0.110

Gnomad AMR AF: 0.0203

Gnomad ASJ AF: 0.0447

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0332

Gnomad FIN AF: 0.0262

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.0388

Gnomad OTH AF: 0.0268

GnomAD2 exomes AF: 0.0288 AC: 4473 AN: 155554 AF XY: 0.0306

Gnomad AFR exome AF: 0.00668

Gnomad AMR exome AF: 0.0152

Gnomad ASJ exome AF: 0.0432

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0256

Gnomad NFE exome AF: 0.0383

Gnomad OTH exome AF: 0.0359

GnomAD4 exome AF: 0.0360 AC: 50380 AN: 1398996 Hom.: 1055 Cov.: 32 AF XY: 0.0362 AC XY: 24985 AN XY: 690012

African (AFR) AF: 0.00567 AC: 179 AN: 31594

American (AMR) AF: 0.0161 AC: 575 AN: 35702

Ashkenazi Jewish (ASJ) AF: 0.0426 AC: 1073 AN: 25182

East Asian (EAS) AF: 0.0000280 AC: 1 AN: 35736

South Asian (SAS) AF: 0.0363 AC: 2872 AN: 79214

European-Finnish (FIN) AF: 0.0280 AC: 1377 AN: 49100

Middle Eastern (MID) AF: 0.0338 AC: 192 AN: 5682

European-Non Finnish (NFE) AF: 0.0391 AC: 42137 AN: 1078792

Other (OTH) AF: 0.0340 AC: 1974 AN: 57994

GnomAD4 genome AF: 0.0262 AC: 3992 AN: 152242 Hom.: 79 Cov.: 32 AF XY: 0.0257 AC XY: 1915 AN XY: 74448

African (AFR) AF: 0.00705 AC: 293 AN: 41554

American (AMR) AF: 0.0203 AC: 310 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.0447 AC: 155 AN: 3468

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5178

South Asian (SAS) AF: 0.0326 AC: 157 AN: 4814

European-Finnish (FIN) AF: 0.0262 AC: 278 AN: 10620

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.0388 AC: 2637 AN: 68000

Other (OTH) AF: 0.0265 AC: 56 AN: 2114

Alfa AF: 0.0334 Hom.: 22

Bravo AF: 0.0249

Asia WGS AF: 0.0130 AC: 47 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 16, 2018

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Autosomal recessive nonsyndromic hearing loss 77 Benign:1

Jul 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
CADD	Benign	6.3
DANN	Benign	0.75
PhyloP100		0.47
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs117403100; hg19: chr18-44104899;