rs328149

Variant names:

• chr18-46590508-G-A
• rs328149
• NM_001384474.1:c.1654+1425C>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.1654+1425C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.795 in 152,156 control chromosomes in the GnomAD database, including 48,561 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 0.79 (48561 hom., cov: 32)
• Consequence: LOXHD1 NM_001384474.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.141
• Publications: 5 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=-0.97).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.856 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LOXHD1	NM_001384474.1	c.1654+1425C>T		intron_variant	Intron 12 of 40	ENST00000642948.1	NP_001371403.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LOXHD1	ENST00000642948.1	c.1654+1425C>T		intron_variant	Intron 12 of 40		NM_001384474.1	ENSP00000496347.1
LOXHD1	ENST00000536736.5	c.1654+1425C>T		intron_variant	Intron 12 of 39	5		ENSP00000444586.1
LOXHD1	ENST00000441551.6	c.1654+1425C>T		intron_variant	Intron 12 of 38	5		ENSP00000387621.2
LOXHD1	ENST00000335730.6	n.967+1425C>T		intron_variant	Intron 5 of 26	2

Frequencies

GnomAD3 genomes AF: 0.795 AC: 120808 AN: 152038 Hom.: 48529 Cov.: 32

Gnomad AFR AF: 0.691

Gnomad AMI AF: 0.942

Gnomad AMR AF: 0.702

Gnomad ASJ AF: 0.811

Gnomad EAS AF: 0.763

Gnomad SAS AF: 0.820

Gnomad FIN AF: 0.890

Gnomad MID AF: 0.797

Gnomad NFE AF: 0.861

Gnomad OTH AF: 0.788

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

GnomAD4 genome AF: 0.795 AC: 120897 AN: 152156 Hom.: 48561 Cov.: 32 AF XY: 0.794 AC XY: 59057 AN XY: 74386

African (AFR) AF: 0.691 AC: 28682 AN: 41486

American (AMR) AF: 0.702 AC: 10722 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.811 AC: 2817 AN: 3472

East Asian (EAS) AF: 0.764 AC: 3955 AN: 5180

South Asian (SAS) AF: 0.820 AC: 3954 AN: 4822

European-Finnish (FIN) AF: 0.890 AC: 9426 AN: 10594

Middle Eastern (MID) AF: 0.813 AC: 239 AN: 294

European-Non Finnish (NFE) AF: 0.861 AC: 58591 AN: 68014

Other (OTH) AF: 0.783 AC: 1652 AN: 2110

Alfa AF: 0.804 Hom.: 7809

Bravo AF: 0.776

Asia WGS AF: 0.751 AC: 2615 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
CADD	Benign	1.7
DANN	Benign	0.53
PhyloP100		0.14
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: rs328149; hg19: chr18-44170471;