chr18-46656943-C-A

Variant names:

• chr18-46656943-C-A
• NM_001384474.1:c.91G>T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001384474.1(LOXHD1):​c.91G>T​(p.Asp31Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000715 in 1,399,306 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/18 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: LOXHD1 NM_001384474.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.780

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.089879245).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LOXHD1	NM_001384474.1	c.91G>T	p.Asp31Tyr	missense_variant	Exon 1 of 41	ENST00000642948.1	NP_001371403.1
LOXHD1	NM_144612.7	c.91G>T	p.Asp31Tyr	missense_variant	Exon 1 of 40		NP_653213.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LOXHD1	ENST00000642948.1	c.91G>T	p.Asp31Tyr	missense_variant	Exon 1 of 41		NM_001384474.1	ENSP00000496347.1
LOXHD1	ENST00000536736.5	c.91G>T	p.Asp31Tyr	missense_variant	Exon 1 of 40	5		ENSP00000444586.1
LOXHD1	ENST00000441551.6	c.91G>T	p.Asp31Tyr	missense_variant	Exon 1 of 39	5		ENSP00000387621.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.15e-7 AC: 1 AN: 1399306 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 690178

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: 0.0000203

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.64
CADD	Benign	18
DANN	Benign	0.77
Eigen	Benign	-0.40
Eigen_PC	Benign	-0.48
FATHMM_MKL	Benign	0.094	N
LIST_S2	Benign	0.76	T;T;T
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.090	T;T;T
MetaSVM	Benign	-1.0	T
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-1.1	N;.;.
REVEL	Benign	0.039
Sift	Benign	0.062	T;.;.
Sift4G	Uncertain	0.060	T;.;T
Polyphen		0.97	D;.;.
Vest4		0.31
MutPred		0.30		Loss of loop (P = 0.0128);Loss of loop (P = 0.0128);Loss of loop (P = 0.0128);
MVP		0.12
ClinPred		0.25	T
GERP RS		1.6
Varity_R		0.075
gMVP		0.85

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr18-44236906;