18-46546946-T-C

Position:

• chr18-46546946-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001384474.1(LOXHD1):​c.3463A>G​(p.Arg1155Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.807 in 1,551,372 control chromosomes in the GnomAD database, including 508,247 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.75 (43171 hom., cov: 32)
  • Exomes 𝑓: 0.81 (465076 hom.)
• Consequence: LOXHD1 NM_001384474.1 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 2.27

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=9.572991E-7).
• BP6: Variant 18-46546946-T-C is Benign according to our data. Variant chr18-46546946-T-C is described in ClinVar as [Benign]. Clinvar id is 47934.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr18-46546946-T-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.826 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LOXHD1	NM_001384474.1	c.3463A>G	p.Arg1155Gly	missense_variant	22/41	ENST00000642948.1	NP_001371403.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LOXHD1	ENST00000642948.1	c.3463A>G	p.Arg1155Gly	missense_variant	22/41		NM_001384474.1	ENSP00000496347.1

Frequencies

GnomAD3 genomes AF: 0.748 AC: 113731 AN: 151982 Hom.: 43156 Cov.: 32

Gnomad AFR AF: 0.634

Gnomad AMI AF: 0.639

Gnomad AMR AF: 0.693

Gnomad ASJ AF: 0.801

Gnomad EAS AF: 0.656

Gnomad SAS AF: 0.749

Gnomad FIN AF: 0.769

Gnomad MID AF: 0.766

Gnomad NFE AF: 0.832

Gnomad OTH AF: 0.776

GnomAD3 exomes AF: 0.757 AC: 119701 AN: 158160 Hom.: 45935 AF XY: 0.765 AC XY: 63701 AN XY: 83316

Gnomad AFR exome AF: 0.630

Gnomad AMR exome AF: 0.627

Gnomad ASJ exome AF: 0.789

Gnomad EAS exome AF: 0.647

Gnomad SAS exome AF: 0.761

Gnomad FIN exome AF: 0.777

Gnomad NFE exome AF: 0.835

Gnomad OTH exome AF: 0.780

GnomAD4 exome AF: 0.813 AC: 1137881 AN: 1399272 Hom.: 465076 Cov.: 60 AF XY: 0.813 AC XY: 561038 AN XY: 690136

Gnomad4 AFR exome AF: 0.624

Gnomad4 AMR exome AF: 0.640

Gnomad4 ASJ exome AF: 0.796

Gnomad4 EAS exome AF: 0.660

Gnomad4 SAS exome AF: 0.759

Gnomad4 FIN exome AF: 0.773

Gnomad4 NFE exome AF: 0.837

Gnomad4 OTH exome AF: 0.799

GnomAD4 genome AF: 0.748 AC: 113793 AN: 152100 Hom.: 43171 Cov.: 32 AF XY: 0.744 AC XY: 55325 AN XY: 74360

Gnomad4 AFR AF: 0.634

Gnomad4 AMR AF: 0.692

Gnomad4 ASJ AF: 0.801

Gnomad4 EAS AF: 0.656

Gnomad4 SAS AF: 0.748

Gnomad4 FIN AF: 0.769

Gnomad4 NFE AF: 0.832

Gnomad4 OTH AF: 0.774

Alfa AF: 0.813 Hom.: 118035

Bravo AF: 0.736

TwinsUK AF: 0.832 AC: 3085

ALSPAC AF: 0.833 AC: 3212

ESP6500AA AF: 0.626 AC: 866

ESP6500EA AF: 0.835 AC: 2657

ExAC AF: 0.754 AC: 18823

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 07, 2012	Arg1155Gly in Exon 22 of LOXHD1: This variant is not expected to have clinical s ignificance because it has been identified in 36.2% (254/702) of African America n chromosomes from a broad population by the NHLBI Exome Sequencing Project (htt p://evs.gs.washington.edu/EVS; dbSNP rs1893566). -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 09, 2017	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Autosomal recessive nonsyndromic hearing loss 77 Benign:4

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 10, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.047
BayesDel_addAF	Benign	-0.69	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	13
DANN	Benign	0.58
DEOGEN2	Benign	0.0023	.;T;.;.;.
Eigen	Benign	-0.77
Eigen_PC	Benign	-0.74
FATHMM_MKL	Benign	0.0040	N
LIST_S2	Benign	0.089	T;T;T;T;T
MetaRNN	Benign	9.6e-7	T;T;T;T;T
MetaSVM	Benign	-1.0	T
PrimateAI	Benign	0.31	T
PROVEAN	Benign	1.1	N;.;N;.;.
REVEL	Benign	0.049
Sift	Benign	0.45	T;.;T;.;.
Sift4G	Benign	0.36	T;T;T;.;T
Polyphen		0.0060	.;.;B;.;.
Vest4		0.071
ClinPred		0.0020	T
GERP RS		4.9
Varity_R		0.18
gMVP		0.57

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: rs1893566; hg19: chr18-44126909;