NM_001384474.1:c.1815C>A

Variant names:

• chr18-46577862-G-T
• rs201388780
• NM_001384474.1:c.1815C>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001384474.1(LOXHD1):​c.1815C>A​(p.Asp605Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. D605D) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: LOXHD1 NM_001384474.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0140
• Publications: 2 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LOXHD1	NM_001384474.1	c.1815C>A	p.Asp605Glu	missense_variant	Exon 14 of 41	ENST00000642948.1	NP_001371403.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LOXHD1	ENST00000642948.1	c.1815C>A	p.Asp605Glu	missense_variant	Exon 14 of 41		NM_001384474.1	ENSP00000496347.1
LOXHD1	ENST00000536736.5	c.1815C>A	p.Asp605Glu	missense_variant	Exon 14 of 40	5		ENSP00000444586.1
LOXHD1	ENST00000441551.6	c.1815C>A	p.Asp605Glu	missense_variant	Exon 14 of 39	5		ENSP00000387621.2
LOXHD1	ENST00000335730.6	n.1128C>A		non_coding_transcript_exon_variant	Exon 7 of 27	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00 AC: 0 AN: 157890 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.88
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.060
CADD	Benign	1.1
DANN	Benign	0.48
Eigen	Benign	-0.73
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.33	N
LIST_S2	Uncertain	0.91	D;D;D
M_CAP	Benign	0.026	D
MetaRNN	Uncertain	0.67	D;D;D
MetaSVM	Uncertain	-0.20	T
PhyloP100		-0.014
PrimateAI	Uncertain	0.65	T
PROVEAN	Uncertain	-3.6	D;.;.
REVEL	Uncertain	0.43
Sift	Pathogenic	0.0	D;.;.
Sift4G	Pathogenic	0.0	D;.;D
Polyphen		1.0	D;.;.
Vest4		0.73
MutPred		0.46		Loss of ubiquitination at K601 (P = 0.0709);Loss of ubiquitination at K601 (P = 0.0709);Loss of ubiquitination at K601 (P = 0.0709);
MVP		0.030
ClinPred		0.98	D
GERP RS		-9.6
Varity_R		0.16
gMVP		0.77
Mutation Taster		=66/34	polymorphism

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: rs201388780; hg19: chr18-44157825;