chr18-46560082-C-G

Variant names:

• chr18-46560082-C-G
• rs537227442
• NM_001384474.1:c.3061+1G>C

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_001384474.1(LOXHD1):​c.3061+1G>C variant causes a splice donor, intron change. The variant allele was found at a frequency of 0.00000178 in 561,890 control chromosomes in the GnomAD database, with no homozygous occurrence. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency:
  • Genomes: not found (cov: 26)
  • Exomes 𝑓: 0.0000018 (0 hom.)
• Consequence: LOXHD1 NM_001384474.1 splice_donor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.17
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• autosomal recessive nonsyndromic hearing loss 77

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, PanelApp Australia, Labcorp Genetics (formerly Invitae), Ambry Genetics
• nonsyndromic genetic hearing loss

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• hearing loss, autosomal recessive

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• Fuchs' endothelial dystrophy

  Inheritance: AD Classification: LIMITED Submitted by: Illumina

ACMG classification

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 18-46560082-C-G is Pathogenic according to our data. Variant chr18-46560082-C-G is described in ClinVar as Pathogenic. ClinVar VariationId is 2027333.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001384474.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LOXHD1	NM_001384474.1	MANE Select	c.3061+1G>C		splice_donor intron	N/A	NP_001371403.1
	LOXHD1	NM_144612.7		c.3061+1G>C		splice_donor intron	N/A	NP_653213.6

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LOXHD1	ENST00000642948.1	MANE Select	c.3061+1G>C		splice_donor intron	N/A	ENSP00000496347.1
	LOXHD1	ENST00000536736.5	TSL:5	c.3061+1G>C		splice_donor intron	N/A	ENSP00000444586.1
	LOXHD1	ENST00000441551.6	TSL:5	c.2599-2593G>C		intron	N/A	ENSP00000387621.2

Frequencies

GnomAD3 genomes Cov.: 26

GnomAD4 exome AF: 0.00000178 AC: 1 AN: 561890 Hom.: 0 Cov.: 28 AF XY: 0.00 AC XY: 0 AN XY: 291912

African (AFR) AF: 0.00 AC: 0 AN: 13498

American (AMR) AF: 0.00 AC: 0 AN: 27994

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 12766

East Asian (EAS) AF: 0.00 AC: 0 AN: 12520

South Asian (SAS) AF: 0.00 AC: 0 AN: 64536

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 29718

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3312

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 374816

Other (OTH) AF: 0.0000440 AC: 1 AN: 22730

GnomAD4 genome Cov.: 26

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Uncertain	0.071	D
BayesDel_noAF	Benign	-0.14
CADD	Pathogenic	35
DANN	Uncertain	0.99
Eigen	Uncertain	0.35
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Pathogenic	0.99	D
PhyloP100		7.2
GERP RS		4.9
Mutation Taster		=0/100	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.93
SpliceAI score (max)		0.99		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.76		Position offset: -3
DS_DL_spliceai		0.99		Position offset: 1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs537227442; hg19: chr18-44140045;