dbSNP rs192376005: LOXHD1:p.Arg524Cys (chr18-46592017-G-A) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 1P and 13B. PP3BP4_StrongBP6BS1BS2

The NM_001384474.1(LOXHD1):c.1570C>T(p.Arg524Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00305 in 1,552,186 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R524H) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0028 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0031 ( 5 hom. )

Consequence

LOXHD1
NM_001384474.1 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5B:9

Conservation

PhyloP100: 9.27

Publications

9 publications found

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 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

LOXHD1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

PP3

Multiple lines of computational evidence support a deleterious effect 7: BayesDel_noAF, Cadd, Eigen, phyloP100way_vertebrate, PROVEAN, REVEL, REVEL [when BayesDel_addAF, max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]

BP4

Computational evidence support a benign effect (MetaRNN=0.024916917).

BP6

Variant 18-46592017-G-A is Benign according to our data. Variant chr18-46592017-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 163930.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00282 (430/152276) while in subpopulation AMR AF = 0.00883 (135/15296). AF 95% confidence interval is 0.00761. There are 1 homozygotes in GnomAd4. There are 214 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 5 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001384474.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LOXHD1	NM_001384474.1	MANE Select	c.1570C>T	p.Arg524Cys	missense	Exon 12 of 41	NP_001371403.1
	LOXHD1	NM_144612.7		c.1570C>T	p.Arg524Cys	missense	Exon 12 of 40	NP_653213.6

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
LOXHD1	ENST00000642948.1	MANE Select	c.1570C>T	p.Arg524Cys	missense	Exon 12 of 41	ENSP00000496347.1
LOXHD1	ENST00000536736.5	TSL:5	c.1570C>T	p.Arg524Cys	missense	Exon 12 of 40	ENSP00000444586.1
LOXHD1	ENST00000441551.6	TSL:5	c.1570C>T	p.Arg524Cys	missense	Exon 12 of 39	ENSP00000387621.2

Frequencies

GnomAD3 genomes

AF:

0.00283

AC:

431

AN:

152158

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000700

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00890

Gnomad ASJ

AF:

0.00173

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00370

Gnomad OTH

AF:

0.00335

GnomAD2 exomes

AF:

0.00274

AC:

440

AN:

160600

AF XY:

0.00254

show subpopulations

Gnomad AFR exome

AF:

0.000769

Gnomad AMR exome

AF:

0.00435

Gnomad ASJ exome

AF:

0.00538

Gnomad EAS exome

AF:

0.0000883

Gnomad FIN exome

AF:

0.000409

Gnomad NFE exome

AF:

0.00398

Gnomad OTH exome

AF:

0.00371

GnomAD4 exome

AF:

0.00308

AC:

4306

AN:

1399910

Hom.:

Cov.:

AF XY:

0.00291

AC XY:

2012

AN XY:

690436

show subpopulations

African (AFR)

AF:

0.000601

AC:

AN:

31594

American (AMR)

AF:

0.00420

AC:

150

AN:

35710

Ashkenazi Jewish (ASJ)

AF:

0.00401

AC:

101

AN:

25180

East Asian (EAS)

AF:

0.0000560

AC:

AN:

35740

South Asian (SAS)

AF:

0.000341

AC:

AN:

79236

European-Finnish (FIN)

AF:

0.000323

AC:

AN:

49510

Middle Eastern (MID)

AF:

0.000175

AC:

AN:

5704

European-Non Finnish (NFE)

AF:

0.00354

AC:

3825

AN:

1079056

Other (OTH)

AF:

0.00284

AC:

165

AN:

58180

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.465

Heterozygous variant carriers

244

488

731

975

1219

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

142

284

426

568

710

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00282

AC:

430

AN:

152276

Hom.:

Cov.:

AF XY:

0.00287

AC XY:

214

AN XY:

74448

show subpopulations

African (AFR)

AF:

0.000698

AC:

AN:

41554

American (AMR)

AF:

0.00883

AC:

135

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.00173

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.000207

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10610

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00370

AC:

252

AN:

68028

Other (OTH)

AF:

0.00331

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.491

Heterozygous variant carriers

107

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00333

Hom.:

Bravo

AF:

0.00312

TwinsUK

AF:

0.00378

AC:

ALSPAC

AF:

0.00311

AC:

ESP6500AA

AF:

0.000723

AC:

ESP6500EA

AF:

0.00314

AC:

ExAC

AF:

0.00168

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

ClinVar submissions as Germline

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (5)

Autosomal recessive nonsyndromic hearing loss 77 (4)

not specified (4)

LOXHD1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.55

BayesDel_addAF

Benign

-0.0054

BayesDel_noAF

Pathogenic

0.22

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

Eigen

Pathogenic

0.97

Eigen_PC

Pathogenic

0.96

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.98

M_CAP

Uncertain

0.13

MetaRNN

Benign

0.025

MetaSVM

Uncertain

-0.021

PhyloP100

9.3

PrimateAI

Uncertain

0.64

PROVEAN

Pathogenic

-6.5

REVEL

Pathogenic

0.66

Sift

Benign

0.17

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.78

MVP

0.72

ClinPred

0.026

GERP RS

6.1

Varity_R

0.43

gMVP

0.75

Mutation Taster

=77/23

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over