chr18-46560281-C-A

Position:

• chr18-46560281-C-A

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_001384474.1(LOXHD1):​c.2863G>T​(p.Glu955Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000143 in 1,399,614 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: LOXHD1 NM_001384474.1 stop_gained
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 1.25

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 Pathogenic. Variant got 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 18-46560281-C-A is Pathogenic according to our data. Variant chr18-46560281-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 1526069.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr18-46560281-C-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LOXHD1	NM_001384474.1	c.2863G>T	p.Glu955Ter	stop_gained	19/41	ENST00000642948.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LOXHD1	ENST00000642948.1	c.2863G>T	p.Glu955Ter	stop_gained	19/41		NM_001384474.1	P1
LOXHD1	ENST00000536736.5	c.2863G>T	p.Glu955Ter	stop_gained	19/40	5
LOXHD1	ENST00000441551.6	c.2598+2784G>T		intron_variant		5
LOXHD1	ENST00000335730.6	n.2176G>T		non_coding_transcript_exon_variant	12/27	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000143 AC: 2 AN: 1399614 Hom.: 0 Cov.: 37 AF XY: 0.00000145 AC XY: 1 AN XY: 690336

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000185

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Autosomal recessive nonsyndromic hearing loss 77 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

3billion

Mar 22, 2022

Stop-gained (nonsense): predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant.It is not observed in the gnomAD v2.1.1 dataset. This variant has been reported to be associated with LOXHD1 related disorder (PMID:23226338). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.048	T
BayesDel_noAF	Benign	-0.31
CADD	Pathogenic	36
DANN	Uncertain	1.0
Eigen	Benign	0.035
Eigen_PC	Benign	0.044
FATHMM_MKL	Uncertain	0.87	D
MutationTaster	Benign	1.0	A;A;D
Vest4		0.23
ClinPred		0.69	D
GERP RS		4.7

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: rs548893604; hg19: chr18-44140244;