rs117403100

Positions:

• chr18-46524936-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001384474.1(LOXHD1):​c.4531-19C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0351 in 1,551,238 control chromosomes in the GnomAD database, including 1,134 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.026 (79 hom., cov: 32)
  • Exomes 𝑓: 0.036 (1055 hom.)
• Consequence: LOXHD1 NM_001384474.1 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.474

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=-0.74).
• BP6: Variant 18-46524936-G-A is Benign according to our data. Variant chr18-46524936-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 262521.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0262 (3992/152242) while in subpopulation NFE AF= 0.0388 (2637/68000). AF 95% confidence interval is 0.0375. There are 79 homozygotes in gnomad4. There are 1915 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 79 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LOXHD1	NM_001384474.1	c.4531-19C>T		intron_variant		ENST00000642948.1	NP_001371403.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LOXHD1	ENST00000642948.1	c.4531-19C>T		intron_variant			NM_001384474.1	ENSP00000496347	P1

Frequencies

GnomAD3 genomes AF: 0.0263 AC: 3996 AN: 152126 Hom.: 80 Cov.: 32

Gnomad AFR AF: 0.00707

Gnomad AMI AF: 0.110

Gnomad AMR AF: 0.0203

Gnomad ASJ AF: 0.0447

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0332

Gnomad FIN AF: 0.0262

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.0388

Gnomad OTH AF: 0.0268

GnomAD3 exomes AF: 0.0288 AC: 4473 AN: 155554 Hom.: 109 AF XY: 0.0306 AC XY: 2512 AN XY: 82000

Gnomad AFR exome AF: 0.00668

Gnomad AMR exome AF: 0.0152

Gnomad ASJ exome AF: 0.0432

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0365

Gnomad FIN exome AF: 0.0256

Gnomad NFE exome AF: 0.0383

Gnomad OTH exome AF: 0.0359

GnomAD4 exome AF: 0.0360 AC: 50380 AN: 1398996 Hom.: 1055 Cov.: 32 AF XY: 0.0362 AC XY: 24985 AN XY: 690012

Gnomad4 AFR exome AF: 0.00567

Gnomad4 AMR exome AF: 0.0161

Gnomad4 ASJ exome AF: 0.0426

Gnomad4 EAS exome AF: 0.0000280

Gnomad4 SAS exome AF: 0.0363

Gnomad4 FIN exome AF: 0.0280

Gnomad4 NFE exome AF: 0.0391

Gnomad4 OTH exome AF: 0.0340

GnomAD4 genome AF: 0.0262 AC: 3992 AN: 152242 Hom.: 79 Cov.: 32 AF XY: 0.0257 AC XY: 1915 AN XY: 74448

Gnomad4 AFR AF: 0.00705

Gnomad4 AMR AF: 0.0203

Gnomad4 ASJ AF: 0.0447

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.0326

Gnomad4 FIN AF: 0.0262

Gnomad4 NFE AF: 0.0388

Gnomad4 OTH AF: 0.0265

Alfa AF: 0.0334 Hom.: 22

Bravo AF: 0.0249

Asia WGS AF: 0.0130 AC: 47 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 16, 2018	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Autosomal recessive nonsyndromic hearing loss 77 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 10, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
CADD	Benign	6.3
DANN	Benign	0.75

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: rs117403100; hg19: chr18-44104899;