rs36024592

Variant names:

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 2P and 16B. PVS1_ModerateBP6_Very_StrongBA1

The NM_001384474.1(LOXHD1):c.2T>A(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0304 in 1,551,572 control chromosomes in the GnomAD database, including 917 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.025 ( 70 hom., cov: 32)

Exomes 𝑓: 0.031 ( 847 hom. )

Consequence

LOXHD1
NM_001384474.1 start_lost

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: 2.84

Publications

16 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 -14 ACMG points.

PVS1

Start lost variant, next in-frame start position is after 1 pathogenic variants. Next in-frame start position is after 2 codons. Genomic position: 46657030. Lost 0.001 part of the original CDS.

BP6

Variant 18-46657032-A-T is Benign according to our data. Variant chr18-46657032-A-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 47932.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0539 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LOXHD1	NM_001384474.1 link	c.2T>A	p.Met1?	start_lost	Exon 1 of 41	ENST00000642948.1	NP_001371403.1
LOXHD1	NM_144612.7 link	c.2T>A	p.Met1?	start_lost	Exon 1 of 40		NP_653213.6	Q8IVV2F5GZB4B7Z7T7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
LOXHD1	ENST00000642948.1 link	c.2T>A	p.Met1?	start_lost	Exon 1 of 41		NM_001384474.1	ENSP00000496347.1	A0A2R8Y7K4
LOXHD1	ENST00000536736.5 link	c.2T>A	p.Met1?	start_lost	Exon 1 of 40	5		ENSP00000444586.1	F5GZB4
LOXHD1	ENST00000441551.6 link	c.2T>A	p.Met1?	start_lost	Exon 1 of 39	5		ENSP00000387621.2	Q8IVV2-1

Frequencies

GnomAD3 genomes

AF:

0.0251

AC:

3825

AN:

152136

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00666

Gnomad AMI

AF:

0.0373

Gnomad AMR

AF:

0.0252

Gnomad ASJ

AF:

0.0675

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0599

Gnomad FIN

AF:

0.0267

Gnomad MID

AF:

0.0348

Gnomad NFE

AF:

0.0330

Gnomad OTH

AF:

0.0325

GnomAD2 exomes

AF:

0.0323

AC:

4970

AN:

154084

AF XY:

0.0353

show subpopulations

Gnomad AFR exome

AF:

0.00517

Gnomad AMR exome

AF:

0.0218

Gnomad ASJ exome

AF:

0.0661

Gnomad EAS exome

AF:

0.000183

Gnomad FIN exome

AF:

0.0218

Gnomad NFE exome

AF:

0.0315

Gnomad OTH exome

AF:

0.0343

GnomAD4 exome

AF:

0.0310

AC:

43398

AN:

1399318

Hom.:

847

Cov.:

AF XY:

0.0323

AC XY:

22273

AN XY:

690184

show subpopulations

African (AFR)

AF:

0.00579

AC:

183

AN:

31598

American (AMR)

AF:

0.0225

AC:

803

AN:

35692

Ashkenazi Jewish (ASJ)

AF:

0.0637

AC:

1604

AN:

25178

East Asian (EAS)

AF:

0.000252

AC:

AN:

35738

South Asian (SAS)

AF:

0.0662

AC:

5244

AN:

79236

European-Finnish (FIN)

AF:

0.0228

AC:

1122

AN:

49276

Middle Eastern (MID)

AF:

0.0365

AC:

208

AN:

5698

European-Non Finnish (NFE)

AF:

0.0300

AC:

32353

AN:

1078902

Other (OTH)

AF:

0.0323

AC:

1872

AN:

58000

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

2574

5148

7723

10297

12871

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1238

2476

3714

4952

6190

<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:

0.0251

AC:

3822

AN:

152254

Hom.:

Cov.:

AF XY:

0.0252

AC XY:

1875

AN XY:

74434

show subpopulations

African (AFR)

AF:

0.00662

AC:

275

AN:

41548

American (AMR)

AF:

0.0252

AC:

385

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.0675

AC:

234

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5158

South Asian (SAS)

AF:

0.0595

AC:

287

AN:

4820

European-Finnish (FIN)

AF:

0.0267

AC:

284

AN:

10628

Middle Eastern (MID)

AF:

0.0340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0330

AC:

2244

AN:

68012

Other (OTH)

AF:

0.0326

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

202

403

605

806

1008

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

138

184

230

<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:

0.0322

Hom.:

Bravo

AF:

0.0232

TwinsUK

AF:

0.0313

AC:

116

ALSPAC

AF:

0.0324

AC:

125

ESP6500AA

AF:

0.00650

AC:

ESP6500EA

AF:

0.0399

AC:

127

ExAC

AF:

0.0374

AC:

952

Asia WGS

AF:

0.0210

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Autosomal recessive nonsyndromic hearing loss 77

Benign:4

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Sep 16, 2020

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Mar 06, 2017

Counsyl

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

Jul 10, 2021

Genome-Nilou Lab

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:3

Dec 20, 2012

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant has been identified in 4% (127/3182) of European American chromosom es from a broad population by the NHLBI Exome Sequencing Project (http://evs.gs. washington.edu/EVS/; dbSNP rs36024592) . There is also a second Met amino acid t hat may serve as the start of translation. -

Aug 25, 2017

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Feb 18, 2022

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: LOXHD1 c.2T>A (p.Met1Lys) alters the initiation codon and is predicted to result either in absence of the protein or truncation of the encoded protein due to translation initiation at a downstream codon. An alternative downstream in-frame start codon (Met2) is located in the encoded protein. One of two in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.032 in 154084 control chromosomes, predominantly at a frequency of 0.064 within the South Asian subpopulation in the gnomAD database, including 69 homozygotes. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 57 fold of the estimated maximal expected allele frequency for a pathogenic variant in LOXHD1 causing Nonsyndromic Hearing Loss And Deafness, Type 77 phenotype (0.0011), strongly suggesting that the variant is a benign polymorphism found primarily in populations of South Asian origin. To our knowledge, no experimental evidence demonstrating its impact on protein function have been reported. Seven ClinVar submitters (evaluation after 2014) cite the variant as benign (n=5) and likely benign (n=2). Based on the evidence outlined above, the variant was classified as benign. -

not provided

Benign:3

Aug 31, 2018

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 27, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.30

BayesDel_noAF

Benign

-0.16

CADD

Benign

(source)

DANN

Benign

0.89

DEOGEN2

Benign

0.014

.;.;T

Eigen

Benign

-0.11

Eigen_PC

Benign

-0.090

FATHMM_MKL

Benign

0.68

LIST_S2

Uncertain

0.90

D;D;D

MetaRNN

Benign

0.0036

T;T;T

MetaSVM

Benign

-0.82

PhyloP100

2.8

PROVEAN

Benign

-0.22

N;.;.

REVEL

Benign

0.22

Sift

Pathogenic

0.0

D;.;.

Sift4G

Pathogenic

0.0

D;.;D

Polyphen

0.60

P;.;.

Vest4

0.33

ClinPred

0.060

GERP RS

4.2

PromoterAI

-0.0074

Neutral

(source)

Varity_R

0.58

gMVP

0.94

Mutation Taster

=99/1

polymorphism (auto)

(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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over