chr18-46503844-C-A

Variant names:

• chr18-46503844-C-A
• rs9957285
• NM_001384474.1:c.5878+1994G>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001384474.1(LOXHD1):​c.5878+1994G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.268 in 151,956 control chromosomes in the GnomAD database, including 6,896 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.27 (6896 hom., cov: 31)
• Consequence: LOXHD1 NM_001384474.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0890
• Publications: 1 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.588 is higher than 0.05.

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.5878+1994G>T		intron	N/A	NP_001371403.1
	LOXHD1	NM_144612.7		c.5692+1994G>T		intron	N/A	NP_653213.6
	LOXHD1	NM_001145472.3		c.2545+1994G>T		intron	N/A	NP_001138944.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LOXHD1	ENST00000642948.1	MANE Select	c.5878+1994G>T		intron	N/A	ENSP00000496347.1
	LOXHD1	ENST00000300591.11	TSL:1	c.2545+1994G>T		intron	N/A	ENSP00000300591.6
	LOXHD1	ENST00000579038.6	TSL:1	c.2257+1994G>T		intron	N/A	ENSP00000463285.1

Frequencies

GnomAD3 genomes AF: 0.268 AC: 40640 AN: 151840 Hom.: 6888 Cov.: 31

Gnomad AFR AF: 0.0797

Gnomad AMI AF: 0.325

Gnomad AMR AF: 0.379

Gnomad ASJ AF: 0.181

Gnomad EAS AF: 0.606

Gnomad SAS AF: 0.240

Gnomad FIN AF: 0.350

Gnomad MID AF: 0.256

Gnomad NFE AF: 0.324

Gnomad OTH AF: 0.298

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.268 AC: 40651 AN: 151956 Hom.: 6896 Cov.: 31 AF XY: 0.271 AC XY: 20114 AN XY: 74262

African (AFR) AF: 0.0795 AC: 3300 AN: 41492

American (AMR) AF: 0.379 AC: 5790 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.181 AC: 629 AN: 3470

East Asian (EAS) AF: 0.606 AC: 3099 AN: 5116

South Asian (SAS) AF: 0.240 AC: 1150 AN: 4800

European-Finnish (FIN) AF: 0.350 AC: 3692 AN: 10556

Middle Eastern (MID) AF: 0.240 AC: 70 AN: 292

European-Non Finnish (NFE) AF: 0.324 AC: 21989 AN: 67938

Other (OTH) AF: 0.301 AC: 636 AN: 2114

Alfa AF: 0.305 Hom.: 4869

Bravo AF: 0.267

Asia WGS AF: 0.381 AC: 1325 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	5.1
DANN	Benign	0.75
PhyloP100		0.089
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs9957285; hg19: chr18-44083807;