rs35727744

Positions:

• chr18-46569606-C-A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001384474.1(LOXHD1):​c.2080G>T​(p.Asp694Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.002 in 1,551,536 control chromosomes in the GnomAD database, including 61 homozygotes. In-silico tool predicts a benign outcome for this variant. 10/17 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 0.011 (33 hom., cov: 33)
  • Exomes 𝑓: 0.0010 (28 hom.)
• Consequence: LOXHD1 NM_001384474.1 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:6
• Conservation: PhyloP100: 2.57

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]

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008591086).
• BP6: Variant 18-46569606-C-A is Benign according to our data. Variant chr18-46569606-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 47924.We mark this variant Likely_benign, oryginal submissions are: {Benign=2, Uncertain_significance=1, Likely_benign=3}.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0109 (1653/152254) while in subpopulation AFR AF= 0.0383 (1591/41540). AF 95% confidence interval is 0.0367. There are 33 homozygotes in gnomad4. There are 781 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 33 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LOXHD1	NM_001384474.1	c.2080G>T	p.Asp694Tyr	missense_variant	16/41	ENST00000642948.1	NP_001371403.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LOXHD1	ENST00000642948.1	c.2080G>T	p.Asp694Tyr	missense_variant	16/41		NM_001384474.1	ENSP00000496347	P1
LOXHD1	ENST00000536736.5	c.2080G>T	p.Asp694Tyr	missense_variant	16/40	5		ENSP00000444586
LOXHD1	ENST00000441551.6	c.2080G>T	p.Asp694Tyr	missense_variant	16/39	5		ENSP00000387621
LOXHD1	ENST00000335730.6	n.1393G>T		non_coding_transcript_exon_variant	9/27	2

Frequencies

GnomAD3 genomes AF: 0.0108 AC: 1648 AN: 152136 Hom.: 32 Cov.: 33

Gnomad AFR AF: 0.0383

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00295

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: 0.0000588

Gnomad OTH AF: 0.00623

GnomAD3 exomes AF: 0.00211 AC: 335 AN: 158540 Hom.: 6 AF XY: 0.00153 AC XY: 128 AN XY: 83474

Gnomad AFR exome AF: 0.0348

Gnomad AMR exome AF: 0.000929

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: 0.0000327

Gnomad OTH exome AF: 0.00156

GnomAD4 exome AF: 0.00104 AC: 1449 AN: 1399282 Hom.: 28 Cov.: 32 AF XY: 0.000874 AC XY: 603 AN XY: 690124

Gnomad4 AFR exome AF: 0.0395

Gnomad4 AMR exome AF: 0.00143

Gnomad4 ASJ exome AF: 0.0000397

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000126

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000324

Gnomad4 OTH exome AF: 0.00184

GnomAD4 genome AF: 0.0109 AC: 1653 AN: 152254 Hom.: 33 Cov.: 33 AF XY: 0.0105 AC XY: 781 AN XY: 74434

Gnomad4 AFR AF: 0.0383

Gnomad4 AMR AF: 0.00294

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.00616

Alfa AF: 0.00433 Hom.: 6

Bravo AF: 0.0122

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.0361 AC: 50

ESP6500EA AF: 0.000314 AC: 1

ExAC AF: 0.00364 AC: 103

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:6

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Autosomal recessive nonsyndromic hearing loss 77 Uncertain:1 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Counsyl	Mar 16, 2017	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Dec 10, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	May 25, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 24, 2018	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

May 07, 2012

Asp694Tyr in Exon 16 of LOXHD1: This variant is not expected to have clinical si gnificance because it has been identified in 3.1% (22/702) of African American c hromosomes from a broad population by the NHLBI Exome Sequencing Project (http:/ /evs.gs.washington.edu/EVS; dbSNP rs35727744). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.28
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	21
DANN	Benign	0.94
Eigen	Uncertain	0.25
Eigen_PC	Uncertain	0.25
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.93	D;D;D
MetaRNN	Benign	0.0086	T;T;T
MetaSVM	Benign	-0.59	T
MutationTaster	Benign	0.93	D;D;D
PrimateAI	Uncertain	0.52	T
PROVEAN	Pathogenic	-6.7	D;.;.
REVEL	Benign	0.22
Sift	Uncertain	0.0060	D;.;.
Sift4G	Uncertain	0.0020	D;.;D
Polyphen		1.0	D;.;.
Vest4		0.52
MVP		0.46
ClinPred		0.045	T
GERP RS		4.8
Varity_R		0.13
gMVP		0.78

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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

Other links and lift over

dbSNP: rs35727744; hg19: chr18-44149569; COSMIC: COSV99046441;