rs115042043

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2BP4_StrongBP6

The NM_001384474.1(LOXHD1):c.2684C>G(p.Thr895Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000139 in 1,542,276 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/16 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00069 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000079 ( 1 hom. )

Consequence

LOXHD1
NM_001384474.1 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:2

Conservation

PhyloP100: 0.896

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.009753555).

BP6

Variant 18-46560460-G-C is Benign according to our data. Variant chr18-46560460-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 227514.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LOXHD1	NM_001384474.1 link	c.2684C>G	p.Thr895Ser	missense_variant	Exon 19 of 41	ENST00000642948.1	NP_001371403.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
LOXHD1	ENST00000642948.1 link	c.2684C>G	p.Thr895Ser	missense_variant	Exon 19 of 41		NM_001384474.1	ENSP00000496347.1	A0A2R8Y7K4
LOXHD1	ENST00000536736.5 link	c.2684C>G	p.Thr895Ser	missense_variant	Exon 19 of 40	5		ENSP00000444586.1	F5GZB4
LOXHD1	ENST00000441551.6 link	c.2598+2605C>G		intron_variant	Intron 18 of 38	5		ENSP00000387621.2	Q8IVV2-1
LOXHD1	ENST00000335730.6 link	n.1997C>G		non_coding_transcript_exon_variant	Exon 12 of 27	2

Frequencies

GnomAD3 genomes

AF:

0.000690

AC:

105

AN:

152132

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00234

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000458

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000234

AC:

AN:

149518

Hom.:

AF XY:

0.000189

AC XY:

AN XY:

79486

show subpopulations

Gnomad AFR exome

AF:

0.00348

Gnomad AMR exome

AF:

0.000121

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000457

GnomAD4 exome

AF:

0.0000791

AC:

110

AN:

1390026

Hom.:

Cov.:

AF XY:

0.0000700

AC XY:

AN XY:

685998

show subpopulations

Gnomad4 AFR exome

AF:

0.00310

Gnomad4 AMR exome

AF:

0.000140

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:

9.27e-7

Gnomad4 OTH exome

AF:

0.000104

GnomAD4 genome

AF:

0.000690

AC:

105

AN:

152250

Hom.:

Cov.:

AF XY:

0.000551

AC XY:

AN XY:

74446

show subpopulations

Gnomad4 AFR

AF:

0.00233

Gnomad4 AMR

AF:

0.000458

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.000379

Hom.:

Bravo

AF:

0.000876

ESP6500AA

AF:

0.00361

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000174

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Aug 02, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2684C>G (p.T895S) alteration is located in exon 19 (coding exon 19) of the LOXHD1 gene. This alteration results from a C to G substitution at nucleotide position 2684, causing the threonine (T) at amino acid position 895 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not specified

Benign:1

Feb 02, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

p.Thr895Ser in exon 19 of LOXHD1: This variant is not expected to have clinical significance because it has been identified in 0.4% (11/2250) of African chromos omes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs115042043). -

not provided

Benign:1

Nov 29, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.59

BayesDel_noAF

Benign

-0.63

CADD

Benign

7.5

DANN

Benign

0.68

Eigen

Benign

-1.0

Eigen_PC

Benign

-0.94

FATHMM_MKL

Benign

0.095

LIST_S2

Benign

0.51

T;T

M_CAP

Benign

0.046

MetaRNN

Benign

0.0098

T;T

MetaSVM

Benign

-1.0

PrimateAI

Benign

0.28

PROVEAN

Benign

-0.47

N;.

REVEL

Benign

0.067

Sift

Benign

0.40

T;.

Sift4G

Benign

0.72

T;.

Polyphen

0.0

B;.

Vest4

0.16

MutPred

0.58

Loss of sheet (P = 0.0315);Loss of sheet (P = 0.0315);

MVP

0.040

ClinPred

0.0056

GERP RS

0.11

gMVP

0.28

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

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