18-46579407-C-T

Variant names:

• chr18-46579407-C-T
• rs16939650
• NM_001384474.1:c.1809+223G>A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001384474.1(LOXHD1):​c.1809+223G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.258 in 152,000 control chromosomes in the GnomAD database, including 5,594 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 0.26 (5594 hom., cov: 32)
• Consequence: LOXHD1 NM_001384474.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.52

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=-0.92).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.319 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LOXHD1	NM_001384474.1	c.1809+223G>A		intron_variant	Intron 13 of 40	ENST00000642948.1	NP_001371403.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LOXHD1	ENST00000642948.1	c.1809+223G>A		intron_variant	Intron 13 of 40		NM_001384474.1	ENSP00000496347.1
LOXHD1	ENST00000536736.5	c.1809+223G>A		intron_variant	Intron 13 of 39	5		ENSP00000444586.1
LOXHD1	ENST00000441551.6	c.1809+223G>A		intron_variant	Intron 13 of 38	5		ENSP00000387621.2
LOXHD1	ENST00000335730.6	n.1122+223G>A		intron_variant	Intron 6 of 26	2

Frequencies

GnomAD3 genomes AF: 0.258 AC: 39205 AN: 151882 Hom.: 5588 Cov.: 32

Gnomad AFR AF: 0.153

Gnomad AMI AF: 0.409

Gnomad AMR AF: 0.276

Gnomad ASJ AF: 0.179

Gnomad EAS AF: 0.269

Gnomad SAS AF: 0.333

Gnomad FIN AF: 0.437

Gnomad MID AF: 0.228

Gnomad NFE AF: 0.287

Gnomad OTH AF: 0.247

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

GnomAD4 genome AF: 0.258 AC: 39221 AN: 152000 Hom.: 5594 Cov.: 32 AF XY: 0.267 AC XY: 19798 AN XY: 74286

Gnomad4 AFR AF: 0.153

Gnomad4 AMR AF: 0.277

Gnomad4 ASJ AF: 0.179

Gnomad4 EAS AF: 0.269

Gnomad4 SAS AF: 0.332

Gnomad4 FIN AF: 0.437

Gnomad4 NFE AF: 0.287

Gnomad4 OTH AF: 0.248

Alfa AF: 0.166 Hom.: 356

Bravo AF: 0.243

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.42
DANN	Benign	0.29

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

Publications

LitVar

Other links and lift over

dbSNP: rs16939650; hg19: chr18-44159370;