rs1450425

chr18-46529070-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.4530+107A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.712 in 1,356,964 control chromosomes in the GnomAD database, including 346,192 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.66 (33931 hom., cov: 29)
  • Exomes 𝑓: 0.72 (312261 hom.)
• Consequence: LOXHD1 NM_001384474.1 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.88

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BP6: Variant 18-46529070-T-C is Benign according to our data. Variant chr18-46529070-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 191090.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.727 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LOXHD1	NM_001384474.1	c.4530+107A>G		intron_variant		ENST00000642948.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LOXHD1	ENST00000642948.1	c.4530+107A>G		intron_variant			NM_001384474.1	P1

Frequencies

GnomAD3 genomes AF: 0.663 AC: 100528 AN: 151542 Hom.: 33920 Cov.: 29

Gnomad AFR AF: 0.547

Gnomad AMI AF: 0.384

Gnomad AMR AF: 0.648

Gnomad ASJ AF: 0.708

Gnomad EAS AF: 0.591

Gnomad SAS AF: 0.676

Gnomad FIN AF: 0.734

Gnomad MID AF: 0.680

Gnomad NFE AF: 0.732

Gnomad OTH AF: 0.669

GnomAD4 exome AF: 0.718 AC: 865381 AN: 1205304 Hom.: 312261 AF XY: 0.718 AC XY: 428587 AN XY: 596972

Gnomad4 AFR exome AF: 0.539

Gnomad4 AMR exome AF: 0.642

Gnomad4 ASJ exome AF: 0.701

Gnomad4 EAS exome AF: 0.620

Gnomad4 SAS exome AF: 0.680

Gnomad4 FIN exome AF: 0.733

Gnomad4 NFE exome AF: 0.733

Gnomad4 OTH exome AF: 0.706

GnomAD4 genome AF: 0.663 AC: 100580 AN: 151660 Hom.: 33931 Cov.: 29 AF XY: 0.662 AC XY: 49070 AN XY: 74086

Gnomad4 AFR AF: 0.547

Gnomad4 AMR AF: 0.648

Gnomad4 ASJ AF: 0.708

Gnomad4 EAS AF: 0.590

Gnomad4 SAS AF: 0.676

Gnomad4 FIN AF: 0.734

Gnomad4 NFE AF: 0.732

Gnomad4 OTH AF: 0.668

Alfa AF: 0.718 Hom.: 51748

Bravo AF: 0.650

Asia WGS AF: 0.660 AC: 2298 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

research

Department Of Translational Genomics (developmental Genetics Section), King Faisal Specialist Hospital & Research Centre

Sep 28, 2016

- -

Autosomal recessive nonsyndromic hearing loss 77 Benign:1

Benign, criteria provided, single submitter

clinical testing

Mendelics

May 28, 2019

- -

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	-0.93
Cadd	Benign	0.43
Dann	Benign	0.41

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: rs1450425; hg19: chr18-44109033; COSMIC: COSV56072333; COSMIC: COSV56072333;