Genetic Variant LOXHD1:p.Arg615Arg (chr18-46577834-G-T) – ACMG Classification: Benign (-11 pts)

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4BP6BP7BS1BS2

The NM_001384474.1(LOXHD1):c.1843C>A(p.Arg615Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.001 in 1,551,590 control chromosomes in the GnomAD database, including 16 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0053 ( 7 hom., cov: 32)

Exomes 𝑓: 0.00054 ( 9 hom. )

Consequence

LOXHD1
NM_001384474.1 synonymous

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:6

Conservation

PhyloP100: 0.880

Publications

6 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 -11 ACMG points.

BP4

Computational evidence support a benign effect (REVEL=0.273).

BP6

Variant 18-46577834-G-T is Benign according to our data. Variant chr18-46577834-G-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 178400.

BP7

Synonymous conserved (PhyloP=0.88 with no splicing effect.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00527 (802/152166) while in subpopulation AFR AF = 0.0183 (758/41526). AF 95% confidence interval is 0.0172. There are 7 homozygotes in GnomAd4. There are 379 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 7 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.1843C>A	p.Arg615Arg	synonymous	Exon 14 of 41	NP_001371403.1	A0A2R8Y7K4
	LOXHD1	NM_144612.7		c.1843C>A	p.Arg615Arg	synonymous	Exon 14 of 40	NP_653213.6

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
LOXHD1	ENST00000642948.1	MANE Select	c.1843C>A	p.Arg615Arg	synonymous	Exon 14 of 41	ENSP00000496347.1	A0A2R8Y7K4
LOXHD1	ENST00000536736.5	TSL:5	c.1843C>A	p.Arg615Arg	synonymous	Exon 14 of 40	ENSP00000444586.1	F5GZB4
LOXHD1	ENST00000441551.6	TSL:5	c.1843C>A	p.Arg615Arg	synonymous	Exon 14 of 39	ENSP00000387621.2	Q8IVV2-1

Frequencies

GnomAD3 genomes

AF:

0.00520

AC:

791

AN:

152048

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0180

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00223

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:

0.000118

Gnomad OTH

AF:

0.000959

GnomAD2 exomes

AF:

0.00108

AC:

171

AN:

158190

AF XY:

0.000732

show subpopulations

Gnomad AFR exome

AF:

0.0163

Gnomad AMR exome

AF:

0.000808

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000822

Gnomad OTH exome

AF:

0.000896

GnomAD4 exome

AF:

0.000538

AC:

753

AN:

1399424

Hom.:

Cov.:

AF XY:

0.000461

AC XY:

318

AN XY:

690212

show subpopulations

African (AFR)

AF:

0.0186

AC:

587

AN:

31598

American (AMR)

AF:

0.000756

AC:

AN:

35704

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25182

East Asian (EAS)

AF:

0.00

AC:

AN:

35738

South Asian (SAS)

AF:

0.0000757

AC:

AN:

79236

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49280

Middle Eastern (MID)

AF:

0.00246

AC:

AN:

5698

European-Non Finnish (NFE)

AF:

0.0000250

AC:

AN:

1078978

Other (OTH)

AF:

0.00159

AC:

AN:

58010

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

Heterozygous variant carriers

128

171

214

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<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:

0.00527

AC:

802

AN:

152166

Hom.:

Cov.:

AF XY:

0.00509

AC XY:

379

AN XY:

74390

show subpopulations

African (AFR)

AF:

0.0183

AC:

758

AN:

41526

American (AMR)

AF:

0.00223

AC:

AN:

15270

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3464

East Asian (EAS)

AF:

0.00

AC:

AN:

5178

South Asian (SAS)

AF:

0.00

AC:

AN:

4816

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10592

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000118

AC:

AN:

68006

Other (OTH)

AF:

0.000949

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

112

149

186

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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:

0.000249

Hom.:

Bravo

AF:

0.00621

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Autosomal recessive nonsyndromic hearing loss 77 (3)

not provided (2)

not specified (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.52

CADD

Benign

2.3

(source)

DANN

Benign

0.43

PhyloP100

0.88

Mutation Taster

=99/1

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