rs143514947

Variant names:

• chr18-46483755-AC-A
• rs143514947
• NM_001384474.1:c.6183-11delG

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_001384474.1(LOXHD1):​c.6183-11delG variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.303 in 1,549,790 control chromosomes in the GnomAD database, including 75,903 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.24 (5227 hom., cov: 23)
  • Exomes 𝑓: 0.31 (70676 hom.)
• Consequence: LOXHD1 NM_001384474.1 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.360
• Publications: 2 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: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
• 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 -16 ACMG points.

• BP6: Variant 18-46483755-AC-A is Benign according to our data. Variant chr18-46483755-AC-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 262524.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.327 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001384474.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LOXHD1	NM_001384474.1	MANE Select	c.6183-11delG		intron	N/A	NP_001371403.1	A0A2R8Y7K4
	LOXHD1	NM_144612.7		c.5997-11delG		intron	N/A	NP_653213.6
	LOXHD1	NM_001145472.3		c.2850-11delG		intron	N/A	NP_001138944.1	Q8IVV2-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LOXHD1	ENST00000642948.1	MANE Select	c.6183-11delG		intron	N/A	ENSP00000496347.1	A0A2R8Y7K4
	LOXHD1	ENST00000300591.11	TSL:1	c.2850-11delG		intron	N/A	ENSP00000300591.6	Q8IVV2-3
	LOXHD1	ENST00000579038.6	TSL:1	c.2562-11delG		intron	N/A	ENSP00000463285.1	J3QKX9

Frequencies

GnomAD3 genomes AF: 0.236 AC: 35887 AN: 151880 Hom.: 5228 Cov.: 23

Gnomad AFR AF: 0.0777

Gnomad AMI AF: 0.351

Gnomad AMR AF: 0.257

Gnomad ASJ AF: 0.250

Gnomad EAS AF: 0.0112

Gnomad SAS AF: 0.254

Gnomad FIN AF: 0.306

Gnomad MID AF: 0.247

Gnomad NFE AF: 0.330

Gnomad OTH AF: 0.259

GnomAD2 exomes AF: 0.263 AC: 41144 AN: 156302 AF XY: 0.267

Gnomad AFR exome AF: 0.0685

Gnomad AMR exome AF: 0.251

Gnomad ASJ exome AF: 0.246

Gnomad EAS exome AF: 0.00826

Gnomad FIN exome AF: 0.300

Gnomad NFE exome AF: 0.332

Gnomad OTH exome AF: 0.302

GnomAD4 exome AF: 0.310 AC: 433923 AN: 1397792 Hom.: 70676 Cov.: 0 AF XY: 0.310 AC XY: 213431 AN XY: 689212

African (AFR) AF: 0.0681 AC: 2152 AN: 31578

American (AMR) AF: 0.258 AC: 9191 AN: 35658

Ashkenazi Jewish (ASJ) AF: 0.250 AC: 6281 AN: 25088

East Asian (EAS) AF: 0.00915 AC: 327 AN: 35724

South Asian (SAS) AF: 0.255 AC: 20188 AN: 79150

European-Finnish (FIN) AF: 0.302 AC: 14882 AN: 49274

Middle Eastern (MID) AF: 0.276 AC: 1511 AN: 5476

European-Non Finnish (NFE) AF: 0.337 AC: 362800 AN: 1077878

Other (OTH) AF: 0.286 AC: 16591 AN: 57966

GnomAD4 genome AF: 0.236 AC: 35876 AN: 151998 Hom.: 5227 Cov.: 23 AF XY: 0.234 AC XY: 17393 AN XY: 74276

African (AFR) AF: 0.0775 AC: 3218 AN: 41520

American (AMR) AF: 0.257 AC: 3918 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.250 AC: 867 AN: 3472

East Asian (EAS) AF: 0.0112 AC: 58 AN: 5170

South Asian (SAS) AF: 0.252 AC: 1210 AN: 4804

European-Finnish (FIN) AF: 0.306 AC: 3225 AN: 10526

Middle Eastern (MID) AF: 0.245 AC: 72 AN: 294

European-Non Finnish (NFE) AF: 0.330 AC: 22447 AN: 67922

Other (OTH) AF: 0.256 AC: 541 AN: 2110

Alfa AF: 0.185 Hom.: 696

Bravo AF: 0.224

Asia WGS AF: 0.160 AC: 558 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Autosomal recessive nonsyndromic hearing loss 77 (1)
-	-	1	Hearing loss, autosomal recessive (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.36
Mutation Taster		=89/11	polymorphism

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

Other links and lift over

dbSNP: rs143514947; hg19: chr18-44063718;