chr18-46642626-C-A

Position:

• chr18-46642626-C-A

Variant summary

Our verdict is Benign. Variant got -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

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 -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/exons	MANE	Protein	UniProt
LOXHD1	NM_001384474.1	c.246-590G>T		intron_variant		ENST00000642948.1	NP_001371403.1
LOXHD1	NM_144612.7	c.246-590G>T		intron_variant			NP_653213.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LOXHD1	ENST00000642948.1	c.246-590G>T		intron_variant			NM_001384474.1	ENSP00000496347.1
LOXHD1	ENST00000536736.5	c.246-590G>T		intron_variant		5		ENSP00000444586.1
LOXHD1	ENST00000441551.6	c.246-590G>T		intron_variant		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

Gnomad4 AFR AF: 0.0831

Gnomad4 AMR AF: 0.183

Gnomad4 ASJ AF: 0.0709

Gnomad4 EAS AF: 0.331

Gnomad4 SAS AF: 0.194

Gnomad4 FIN AF: 0.0544

Gnomad4 NFE AF: 0.0755

Gnomad4 OTH AF: 0.0937

Alfa AF: 0.0846 Hom.: 666

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

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

Publications

LitVar

Other links and lift over

dbSNP: rs16939868; hg19: chr18-44222589;