dbSNP rs376467400: LOXHD1:p.Arg96Pro (chr18-46641995-C-G) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_001384474.1(LOXHD1):c.287G>C(p.Arg96Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000143 in 1,399,996 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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: 0.0000014 ( 0 hom. )

Consequence

LOXHD1
NM_001384474.1 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.54

Variant links:

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 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.814

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LOXHD1	NM_001384474.1 link	c.287G>C	p.Arg96Pro	missense_variant	Exon 3 of 41	ENST00000642948.1	NP_001371403.1
LOXHD1	NM_144612.7 link	c.287G>C	p.Arg96Pro	missense_variant	Exon 3 of 40		NP_653213.6	Q8IVV2F5GZB4B7Z7T7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
LOXHD1	ENST00000642948.1 link	c.287G>C	p.Arg96Pro	missense_variant	Exon 3 of 41		NM_001384474.1	ENSP00000496347.1	A0A2R8Y7K4
LOXHD1	ENST00000536736.5 link	c.287G>C	p.Arg96Pro	missense_variant	Exon 3 of 40	5		ENSP00000444586.1	F5GZB4
LOXHD1	ENST00000441551.6 link	c.287G>C	p.Arg96Pro	missense_variant	Exon 3 of 39	5		ENSP00000387621.2	Q8IVV2-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000143

AC:

AN:

1399996

Hom.:

Cov.:

AF XY:

0.00000145

AC XY:

AN XY:

690476

show subpopulations

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:

0.00

Gnomad4 NFE exome

AF:

0.00000185

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.89

BayesDel_addAF

Pathogenic

0.32

BayesDel_noAF

Pathogenic

0.22

CADD

Uncertain

DANN

Benign

0.97

Eigen

Pathogenic

0.72

Eigen_PC

Pathogenic

0.71

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.86

D;D;D

M_CAP

Benign

0.042

MetaRNN

Pathogenic

0.81

D;D;D

MetaSVM

Benign

-0.35

PrimateAI

Uncertain

0.73

PROVEAN

Uncertain

-3.1

D;.;.

REVEL

Uncertain

0.57

Sift

Benign

0.069

T;.;.

Sift4G

Uncertain

0.0040

D;.;D

Polyphen

1.0

D;.;.

Vest4

0.87

MutPred

0.63

Loss of MoRF binding (P = 0.0082);Loss of MoRF binding (P = 0.0082);Loss of MoRF binding (P = 0.0082);

MVP

0.41

ClinPred

0.90

GERP RS

5.6

Varity_R

0.61

gMVP

0.86

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over