rs16939868

Variant names:

• chr18-46642626-C-A
• rs16939868
• NM_001384474.1:c.246-590G>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001384474.1(LOXHD1):​c.246-590G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0999 in 152,272 control chromosomes in the GnomAD database, including 1,009 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.10 (1009 hom., cov: 33)
• Consequence: LOXHD1 NM_001384474.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0600
• 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: 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.318 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LOXHD1	NM_001384474.1	c.246-590G>T		intron_variant	Intron 2 of 40	ENST00000642948.1	NP_001371403.1
LOXHD1	NM_144612.7	c.246-590G>T		intron_variant	Intron 2 of 39		NP_653213.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LOXHD1	ENST00000642948.1	c.246-590G>T		intron_variant	Intron 2 of 40		NM_001384474.1	ENSP00000496347.1
LOXHD1	ENST00000536736.5	c.246-590G>T		intron_variant	Intron 2 of 39	5		ENSP00000444586.1
LOXHD1	ENST00000441551.6	c.246-590G>T		intron_variant	Intron 2 of 38	5		ENSP00000387621.2

Frequencies

GnomAD3 genomes AF: 0.0999 AC: 15201 AN: 152152 Hom.: 1008 Cov.: 33

Gnomad AFR AF: 0.0833

Gnomad AMI AF: 0.140

Gnomad AMR AF: 0.183

Gnomad ASJ AF: 0.0709

Gnomad EAS AF: 0.331

Gnomad SAS AF: 0.192

Gnomad FIN AF: 0.0544

Gnomad MID AF: 0.101

Gnomad NFE AF: 0.0755

Gnomad OTH AF: 0.0908

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.0999 AC: 15211 AN: 152272 Hom.: 1009 Cov.: 33 AF XY: 0.104 AC XY: 7779 AN XY: 74470

African (AFR) AF: 0.0831 AC: 3451 AN: 41538

American (AMR) AF: 0.183 AC: 2804 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.0709 AC: 246 AN: 3472

East Asian (EAS) AF: 0.331 AC: 1712 AN: 5174

South Asian (SAS) AF: 0.194 AC: 934 AN: 4824

European-Finnish (FIN) AF: 0.0544 AC: 578 AN: 10616

Middle Eastern (MID) AF: 0.0884 AC: 26 AN: 294

European-Non Finnish (NFE) AF: 0.0755 AC: 5134 AN: 68034

Other (OTH) AF: 0.0937 AC: 198 AN: 2114

Alfa AF: 0.0887 Hom.: 1134

Bravo AF: 0.108

Asia WGS AF: 0.260 AC: 900 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	11
DANN	Benign	0.73
PhyloP100		0.060
Mutation Taster		=100/0	polymorphism (auto)

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: rs16939868; hg19: chr18-44222589;