Variant 18-46477200-C-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001145472.3(LOXHD1):c.3328G>T(p.Ala1110Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000175 in 570,004 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 11/14 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000018 ( 0 hom. )

Consequence

LOXHD1
NM_001145472.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.571

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 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.070946366).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	Protein	UniProt
LOXHD1	NM_001145472.3 linkuse as main transcript	c.3328G>T	p.Ala1110Ser	missense_variant	24/24	NP_001138944.1	Q8IVV2-3
LOXHD1	NM_001308013.2 linkuse as main transcript	c.*18G>T		3_prime_UTR_variant	22/22	NP_001294942.1	J3QKX9
LOXHD1	NM_001173129.2 linkuse as main transcript	c.*18G>T		3_prime_UTR_variant	10/10	NP_001166600.1	Q8IVV2-4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	Protein	UniProt
LOXHD1	ENST00000300591.11 linkuse as main transcript	c.3328G>T	p.Ala1110Ser	missense_variant	24/24	1	ENSP00000300591.6	Q8IVV2-3
LOXHD1	ENST00000579038 linkuse as main transcript	c.*18G>T		3_prime_UTR_variant	22/22	1	ENSP00000463285.1	J3QKX9
LOXHD1	ENST00000398705 linkuse as main transcript	c.*18G>T		3_prime_UTR_variant	10/10	2	ENSP00000381692.2	Q8IVV2-4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000639

AC:

AN:

156542

Hom.:

AF XY:

0.00

AC XY:

AN XY:

82966

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000917

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000175

AC:

AN:

570004

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

307350

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000311

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ExAC

AF:

0.0000409

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jun 11, 2013

Variant classified as Uncertain Significance - Favor Benign. The Ala1110Ser vari ant in LOXHD1 has not been reported in individuals with hearing loss or in large population studies. Computational analyses (biochemical amino acid properties, conservation, AlignGVGD, PolyPhen2, and SIFT) suggest that the Ala1110Ser varia nt may not impact the protein, though this information is not predictive enough to rule out pathogenicity. In summary, the clinical significance of this variant cannot be determined with certainty; however, based upon computational and cons ervation data, we lean towards a more likely benign role. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.35

BayesDel_noAF

Benign

-0.53

CADD

Benign

DANN

Benign

0.97

Eigen

Benign

-0.48

Eigen_PC

Benign

-0.59

FATHMM_MKL

Benign

0.055

LIST_S2

Benign

0.40

M_CAP

Benign

0.027

MetaRNN

Benign

0.071

MetaSVM

Benign

-1.0

PROVEAN

Benign

0.090

REVEL

Benign

0.024

Sift

Pathogenic

0.0

Sift4G

Benign

0.26

Vest4

0.38

MutPred

0.25

Loss of helix (P = 0.0444);

MVP

0.030

ClinPred

0.60

GERP RS

3.1

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over