rs1824683

Variant names:

• chr18-46569957-T-C
• rs1824683
• NM_001384474.1:c.2048-319A>G

Variant summary

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

The NM_001384474.1(LOXHD1):​c.2048-319A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.272 in 152,140 control chromosomes in the GnomAD database, including 6,494 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 0.27 (6494 hom., cov: 33)
• Consequence: LOXHD1 NM_001384474.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.41
• Publications: 3 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=-0.91).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.42 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LOXHD1	NM_001384474.1	c.2048-319A>G		intron_variant	Intron 15 of 40	ENST00000642948.1	NP_001371403.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LOXHD1	ENST00000642948.1	c.2048-319A>G		intron_variant	Intron 15 of 40		NM_001384474.1	ENSP00000496347.1
LOXHD1	ENST00000536736.5	c.2048-319A>G		intron_variant	Intron 15 of 39	5		ENSP00000444586.1
LOXHD1	ENST00000441551.6	c.2048-319A>G		intron_variant	Intron 15 of 38	5		ENSP00000387621.2
LOXHD1	ENST00000335730.6	n.1361-319A>G		intron_variant	Intron 8 of 26	2

Frequencies

GnomAD3 genomes AF: 0.271 AC: 41242 AN: 152022 Hom.: 6464 Cov.: 33

Gnomad AFR AF: 0.424

Gnomad AMI AF: 0.302

Gnomad AMR AF: 0.206

Gnomad ASJ AF: 0.247

Gnomad EAS AF: 0.0753

Gnomad SAS AF: 0.241

Gnomad FIN AF: 0.161

Gnomad MID AF: 0.272

Gnomad NFE AF: 0.228

Gnomad OTH AF: 0.272

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

GnomAD4 genome AF: 0.272 AC: 41328 AN: 152140 Hom.: 6494 Cov.: 33 AF XY: 0.264 AC XY: 19619 AN XY: 74382

African (AFR) AF: 0.425 AC: 17629 AN: 41476

American (AMR) AF: 0.206 AC: 3142 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.247 AC: 857 AN: 3470

East Asian (EAS) AF: 0.0750 AC: 389 AN: 5184

South Asian (SAS) AF: 0.242 AC: 1170 AN: 4826

European-Finnish (FIN) AF: 0.161 AC: 1704 AN: 10590

Middle Eastern (MID) AF: 0.282 AC: 83 AN: 294

European-Non Finnish (NFE) AF: 0.228 AC: 15500 AN: 67994

Other (OTH) AF: 0.275 AC: 579 AN: 2108

Alfa AF: 0.241 Hom.: 3112

Bravo AF: 0.281

Asia WGS AF: 0.190 AC: 661 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	2.0
DANN	Benign	0.46
PhyloP100		-1.4
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: rs1824683; hg19: chr18-44149920;