rs142931455

chr18-46477188-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The ENST00000300591.11(LOXHD1):c.3340G>A(p.Gly1114Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00136 in 720,570 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/14 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0011 (3 hom., cov: 33)
  • Exomes 𝑓: 0.0014 (5 hom.)
• Consequence: LOXHD1 ENST00000300591.11 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.00800

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0057053566).
• BP6: Variant 18-46477188-C-T is Benign according to our data. Variant chr18-46477188-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 178389.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr18-46477188-C-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.00142 (808/568254) while in subpopulation MID AF= 0.00931 (38/4080). AF 95% confidence interval is 0.00698. There are 5 homozygotes in gnomad4_exome. There are 431 alleles in male gnomad4_exome subpopulation. Median coverage is 4. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LOXHD1	NM_001145472.3	c.3340G>A	p.Gly1114Arg	missense_variant	24/24
LOXHD1	NM_001173129.2	c.*30G>A		3_prime_UTR_variant	10/10
LOXHD1	NM_001308013.2	c.*30G>A		3_prime_UTR_variant	22/22

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LOXHD1	ENST00000300591.11	c.3340G>A	p.Gly1114Arg	missense_variant	24/24	1
LOXHD1	ENST00000579038.6	c.*30G>A		3_prime_UTR_variant	22/22	1
LOXHD1	ENST00000398705.7	c.*30G>A		3_prime_UTR_variant	10/10	2

Frequencies

GnomAD3 genomes AF: 0.00113 AC: 172 AN: 152198 Hom.: 3 Cov.: 33

Gnomad AFR AF: 0.000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00111

Gnomad ASJ AF: 0.0156

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.000941

Gnomad OTH AF: 0.00526

GnomAD3 exomes AF: 0.00154 AC: 241 AN: 156552 Hom.: 0 AF XY: 0.00134 AC XY: 111 AN XY: 82978

Gnomad AFR exome AF: 0.000505

Gnomad AMR exome AF: 0.00138

Gnomad ASJ exome AF: 0.0147

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000307

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000892

Gnomad OTH exome AF: 0.00387

GnomAD4 exome AF: 0.00142 AC: 808 AN: 568254 Hom.: 5 Cov.: 4 AF XY: 0.00141 AC XY: 431 AN XY: 306484

Gnomad4 AFR exome AF: 0.000821

Gnomad4 AMR exome AF: 0.00144

Gnomad4 ASJ exome AF: 0.0145

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000318

Gnomad4 FIN exome AF: 0.0000204

Gnomad4 NFE exome AF: 0.000922

Gnomad4 OTH exome AF: 0.00328

GnomAD4 genome AF: 0.00115 AC: 175 AN: 152316 Hom.: 3 Cov.: 33 AF XY: 0.00107 AC XY: 80 AN XY: 74470

Gnomad4 AFR AF: 0.000553

Gnomad4 AMR AF: 0.00111

Gnomad4 ASJ AF: 0.0156

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000941

Gnomad4 OTH AF: 0.00520

Alfa AF: 0.00152 Hom.: 2

Bravo AF: 0.00129

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000519 AC: 2

ExAC AF: 0.00162 AC: 40

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 17, 2018	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2023	LOXHD1: BP4, BS1, BS2 -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Nov 25, 2015

p.Gly1114Arg in exon 40 of LOXHD1: This variant is not expected to have clinical significance because it has been identified in 0.39% (34/8752) of European chro mosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.or g; dbSNP rs142931455). -

LOXHD1-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 13, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.52
Cadd	Benign	6.7
Dann	Benign	0.87
Eigen	Benign	-0.45
Eigen_PC	Benign	-0.59
FATHMM_MKL	Benign	0.044	N
LIST_S2	Benign	0.53	T
M_CAP	Benign	0.051	D
MetaRNN	Benign	0.0057	T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	N;N;N;N
PROVEAN	Benign	0.51	N
REVEL	Benign	0.011
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Vest4		0.22
MutPred		0.43		Gain of solvent accessibility (P = 0.0037);
MVP		0.11
ClinPred		0.017	T
GERP RS		1.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs142931455; hg19: chr18-44057151;