rs142960762

Variant names:

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP3BP6_Very_StrongBS1BS2

The NM_001384474.1(LOXHD1):c.2825_2827delAGA(p.Lys942del) variant causes a disruptive inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0185 in 1,551,740 control chromosomes in the GnomAD database, including 370 homozygotes. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. K942K) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.014 ( 24 hom., cov: 31)

Exomes 𝑓: 0.019 ( 346 hom. )

Consequence

LOXHD1
NM_001384474.1 disruptive_inframe_deletion

Scores

Not classified

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 2.27

Publications

7 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: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
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 -17 ACMG points.

BP3

Nonframeshift variant in repetitive region in NM_001384474.1

BP6

Variant 18-46560316-CTCT-C is Benign according to our data. Variant chr18-46560316-CTCT-C is described in ClinVar as Benign. ClinVar VariationId is 226714.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.0142 (2156/152250) while in subpopulation SAS AF = 0.0409 (197/4818). AF 95% confidence interval is 0.0362. There are 24 homozygotes in GnomAd4. There are 1005 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 24 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.2825_2827delAGA	p.Lys942del	disruptive_inframe_deletion	Exon 19 of 41	NP_001371403.1	A0A2R8Y7K4
	LOXHD1	NM_144612.7		c.2825_2827delAGA	p.Lys942del	disruptive_inframe_deletion	Exon 19 of 40	NP_653213.6

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
LOXHD1	ENST00000642948.1	MANE Select	c.2825_2827delAGA	p.Lys942del	disruptive_inframe_deletion	Exon 19 of 41	ENSP00000496347.1	A0A2R8Y7K4
LOXHD1	ENST00000536736.5	TSL:5	c.2825_2827delAGA	p.Lys942del	disruptive_inframe_deletion	Exon 19 of 40	ENSP00000444586.1	F5GZB4
LOXHD1	ENST00000441551.6	TSL:5	c.2598+2746_2598+2748delAGA		intron	N/A	ENSP00000387621.2	Q8IVV2-1

Frequencies

GnomAD3 genomes

AF:

0.0142

AC:

2154

AN:

152134

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00367

Gnomad AMI

AF:

0.0626

Gnomad AMR

AF:

0.00727

Gnomad ASJ

AF:

0.0280

Gnomad EAS

AF:

0.00986

Gnomad SAS

AF:

0.0406

Gnomad FIN

AF:

0.00424

Gnomad MID

AF:

0.0222

Gnomad NFE

AF:

0.0206

Gnomad OTH

AF:

0.0172

GnomAD2 exomes

AF:

0.0182

AC:

2865

AN:

157278

AF XY:

0.0202

show subpopulations

Gnomad AFR exome

AF:

0.00384

Gnomad AMR exome

AF:

0.00698

Gnomad ASJ exome

AF:

0.0281

Gnomad EAS exome

AF:

0.00731

Gnomad FIN exome

AF:

0.00492

Gnomad NFE exome

AF:

0.0209

Gnomad OTH exome

AF:

0.0175

GnomAD4 exome

AF:

0.0190

AC:

26562

AN:

1399490

Hom.:

346

AF XY:

0.0200

AC XY:

13780

AN XY:

690308

show subpopulations

African (AFR)

AF:

0.00377

AC:

119

AN:

31606

American (AMR)

AF:

0.00781

AC:

279

AN:

35712

Ashkenazi Jewish (ASJ)

AF:

0.0293

AC:

739

AN:

25182

East Asian (EAS)

AF:

0.0265

AC:

946

AN:

35754

South Asian (SAS)

AF:

0.0403

AC:

3192

AN:

79236

European-Finnish (FIN)

AF:

0.00497

AC:

245

AN:

49298

Middle Eastern (MID)

AF:

0.0437

AC:

249

AN:

5702

European-Non Finnish (NFE)

AF:

0.0182

AC:

19611

AN:

1078908

Other (OTH)

AF:

0.0203

AC:

1182

AN:

58092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

1774

3548

5323

7097

8871

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

734

1468

2202

2936

3670

<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:

0.0142

AC:

2156

AN:

152250

Hom.:

Cov.:

AF XY:

0.0135

AC XY:

1005

AN XY:

74418

show subpopulations

African (AFR)

AF:

0.00366

AC:

152

AN:

41550

American (AMR)

AF:

0.00726

AC:

111

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.0280

AC:

AN:

3470

East Asian (EAS)

AF:

0.00988

AC:

AN:

5160

South Asian (SAS)

AF:

0.0409

AC:

197

AN:

4818

European-Finnish (FIN)

AF:

0.00424

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.0238

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0206

AC:

1403

AN:

68020

Other (OTH)

AF:

0.0170

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

112

224

337

449

561

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

112

140

<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:

0.0192

Hom.:

Bravo

AF:

0.0131

Asia WGS

AF:

0.0170

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (4)

Autosomal recessive nonsyndromic hearing loss 77 (2)

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

2.3

Mutation Taster

=61/39

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over