rs761010290

chr18-46560303-G-A

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 2P and 13B. PM2 BP4_Strong BP6_Very_Strong BP7

The NM_001384474.1(LOXHD1):c.2841C>T(p.Asp947=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000419 in 1,551,234 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 0.000046 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000041 (0 hom.)
• Consequence: LOXHD1 NM_001384474.1 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.910

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 -11 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.75).
• BP6: Variant 18-46560303-G-A is Benign according to our data. Variant chr18-46560303-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 262518.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.91 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LOXHD1	NM_001384474.1	c.2841C>T	p.Asp947=	synonymous_variant	19/41	ENST00000642948.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LOXHD1	ENST00000642948.1	c.2841C>T	p.Asp947=	synonymous_variant	19/41		NM_001384474.1	P1
LOXHD1	ENST00000536736.5	c.2841C>T	p.Asp947=	synonymous_variant	19/40	5
LOXHD1	ENST00000441551.6	c.2598+2762C>T		intron_variant		5
LOXHD1	ENST00000335730.6	n.2154C>T		non_coding_transcript_exon_variant	12/27	2

Frequencies

GnomAD3 genomes AF: 0.0000461 AC: 7 AN: 151884 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000484

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000416

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000888 AC: 14 AN: 157704 Hom.: 0 AF XY: 0.000120 AC XY: 10 AN XY: 83066

Gnomad AFR exome AF: 0.000226

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000307

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000656

Gnomad OTH exome AF: 0.000222

GnomAD4 exome AF: 0.0000415 AC: 58 AN: 1399232 Hom.: 0 Cov.: 37 AF XY: 0.0000507 AC XY: 35 AN XY: 690180

Gnomad4 AFR exome AF: 0.0000949

Gnomad4 AMR exome AF: 0.0000280

Gnomad4 ASJ exome AF: 0.0000794

Gnomad4 EAS exome AF: 0.0000280

Gnomad4 SAS exome AF: 0.000265

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000102

Gnomad4 OTH exome AF: 0.000120

GnomAD4 genome AF: 0.0000461 AC: 7 AN: 152002 Hom.: 0 Cov.: 32 AF XY: 0.0000807 AC XY: 6 AN XY: 74308

Gnomad4 AFR AF: 0.0000482

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000416

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000902 Hom.: 0

Bravo AF: 0.0000453

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Aug 10, 2017	p.Asp947Asp in exon 19 of LOXHD1: This variant is not expected to have clinical significance because it does not alter an amino acid residue and is not located within the splice consensus sequence. It has been identified in 0.04% (8/22824) of South Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gn omad.broadinstitute.org; dbSNP rs761010290). -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Autosomal recessive nonsyndromic hearing loss 77 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Counsyl

Jun 05, 2018

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 21, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
Cadd	Benign	0.56
Dann	Benign	0.54

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: rs761010290; hg19: chr18-44140266;