rs114736976

Positions:

• chr18-46521199-G-A

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 2P and 17B. PM2 BP4_Strong BP6_Very_Strong BP7 BS1

The NM_001384474.1(LOXHD1):​c.5169C>T​(p.Tyr1723=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00032 in 1,551,746 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0017 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00017 (0 hom.)
• Consequence: LOXHD1 NM_001384474.1 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.51

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 -15 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.52).
• BP6: Variant 18-46521199-G-A is Benign according to our data. Variant chr18-46521199-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 163900.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.51 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00169 (258/152300) while in subpopulation AFR AF= 0.00606 (252/41566). AF 95% confidence interval is 0.00545. There are 0 homozygotes in gnomad4. There are 110 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LOXHD1	NM_001384474.1	c.5169C>T	p.Tyr1723=	synonymous_variant	33/41	ENST00000642948.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LOXHD1	ENST00000642948.1	c.5169C>T	p.Tyr1723=	synonymous_variant	33/41		NM_001384474.1	P1

Frequencies

GnomAD3 genomes AF: 0.00166 AC: 252 AN: 152182 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00594

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

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: 0.0000294

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000415 AC: 65 AN: 156510 Hom.: 0 AF XY: 0.000326 AC XY: 27 AN XY: 82940

Gnomad AFR exome AF: 0.00719

Gnomad AMR exome AF: 0.000243

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000439

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000228

GnomAD4 exome AF: 0.000171 AC: 239 AN: 1399446 Hom.: 0 Cov.: 31 AF XY: 0.000159 AC XY: 110 AN XY: 690230

Gnomad4 AFR exome AF: 0.00630

Gnomad4 AMR exome AF: 0.000308

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000631

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000278

Gnomad4 OTH exome AF: 0.000362

GnomAD4 genome AF: 0.00169 AC: 258 AN: 152300 Hom.: 0 Cov.: 32 AF XY: 0.00148 AC XY: 110 AN XY: 74468

Gnomad4 AFR AF: 0.00606

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.00117 Hom.: 0

Bravo AF: 0.00203

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 28, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jul 28, 2013	Tyr612Tyr in Exon 32 LOXHD1: This variant is not expected to have clinical signi ficance because it does not alter an amino acid residue, is not located within t he splice consensus sequence, and has been identified in 1.2% (6/490) of African chromosomes by the 1000 Genomes Project and 0.2% (3/1384) of African American c hromosomes by the NHLBI Exome sequencing project (http://evs.gs.washington.edu/E VS/; dbSNP rs114736976). -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jul 20, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.52
CADD	Benign	1.1
DANN	Benign	0.23

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

LitVar

Other links and lift over

dbSNP: rs114736976; hg19: chr18-44101162;