rs1824682

Positions:

• chr18-46569740-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001384474.1(LOXHD1):​c.2048-102A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.231 in 892,746 control chromosomes in the GnomAD database, including 25,623 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.27 (6183 hom., cov: 32)
  • Exomes 𝑓: 0.22 (19440 hom.)
• Consequence: LOXHD1 NM_001384474.1 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -3.04

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.94).
• BP6: Variant 18-46569740-T-C is Benign according to our data. Variant chr18-46569740-T-C is described in ClinVar as [Benign]. Clinvar id is 1184659.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.403 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LOXHD1	NM_001384474.1	c.2048-102A>G		intron_variant		ENST00000642948.1	NP_001371403.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LOXHD1	ENST00000642948.1	c.2048-102A>G		intron_variant			NM_001384474.1	ENSP00000496347.1
LOXHD1	ENST00000536736.5	c.2048-102A>G		intron_variant		5		ENSP00000444586.1
LOXHD1	ENST00000441551.6	c.2048-102A>G		intron_variant		5		ENSP00000387621.2
LOXHD1	ENST00000335730.6	n.1361-102A>G		intron_variant		2

Frequencies

GnomAD3 genomes AF: 0.266 AC: 40458 AN: 151908 Hom.: 6150 Cov.: 32

Gnomad AFR AF: 0.407

Gnomad AMI AF: 0.302

Gnomad AMR AF: 0.205

Gnomad ASJ AF: 0.247

Gnomad EAS AF: 0.0742

Gnomad SAS AF: 0.241

Gnomad FIN AF: 0.161

Gnomad MID AF: 0.272

Gnomad NFE AF: 0.228

Gnomad OTH AF: 0.271

GnomAD4 exome AF: 0.224 AC: 166026 AN: 740720 Hom.: 19440 AF XY: 0.225 AC XY: 83935 AN XY: 372988

Gnomad4 AFR exome AF: 0.415

Gnomad4 AMR exome AF: 0.156

Gnomad4 ASJ exome AF: 0.252

Gnomad4 EAS exome AF: 0.0642

Gnomad4 SAS exome AF: 0.253

Gnomad4 FIN exome AF: 0.154

Gnomad4 NFE exome AF: 0.231

Gnomad4 OTH exome AF: 0.237

GnomAD4 genome AF: 0.267 AC: 40550 AN: 152026 Hom.: 6183 Cov.: 32 AF XY: 0.260 AC XY: 19302 AN XY: 74324

Gnomad4 AFR AF: 0.408

Gnomad4 AMR AF: 0.205

Gnomad4 ASJ AF: 0.247

Gnomad4 EAS AF: 0.0740

Gnomad4 SAS AF: 0.242

Gnomad4 FIN AF: 0.161

Gnomad4 NFE AF: 0.228

Gnomad4 OTH AF: 0.274

Alfa AF: 0.239 Hom.: 2139

Bravo AF: 0.276

Asia WGS AF: 0.190 AC: 661 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Autosomal recessive nonsyndromic hearing loss 77 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 10, 2021

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

May 12, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	0.013
DANN	Benign	0.21

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: rs1824682; hg19: chr18-44149703;