rs16978578

Positions:

• chr18-46572106-T-C

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.2027A>G​(p.Asp676Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00135 in 1,551,826 control chromosomes in the GnomAD database, including 30 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/17 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 0.0070 (12 hom., cov: 31)
  • Exomes 𝑓: 0.00073 (18 hom.)
• Consequence: LOXHD1 NM_001384474.1 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4
• Conservation: PhyloP100: 0.967

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=0.0026506186).
• BP6: Variant 18-46572106-T-C is Benign according to our data. Variant chr18-46572106-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 226712.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Benign=2, Uncertain_significance=1}.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00704 (1073/152334) while in subpopulation AFR AF= 0.0246 (1022/41578). AF 95% confidence interval is 0.0233. There are 12 homozygotes in gnomad4. There are 505 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 12 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LOXHD1	NM_001384474.1	c.2027A>G	p.Asp676Gly	missense_variant	15/41	ENST00000642948.1	NP_001371403.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LOXHD1	ENST00000642948.1	c.2027A>G	p.Asp676Gly	missense_variant	15/41		NM_001384474.1	ENSP00000496347	P1
LOXHD1	ENST00000536736.5	c.2027A>G	p.Asp676Gly	missense_variant	15/40	5		ENSP00000444586
LOXHD1	ENST00000441551.6	c.2027A>G	p.Asp676Gly	missense_variant	15/39	5		ENSP00000387621
LOXHD1	ENST00000335730.6	n.1340A>G		non_coding_transcript_exon_variant	8/27	2

Frequencies

GnomAD3 genomes AF: 0.00704 AC: 1071 AN: 152216 Hom.: 12 Cov.: 31

Gnomad AFR AF: 0.0246

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00249

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.00152 AC: 241 AN: 158922 Hom.: 3 AF XY: 0.00114 AC XY: 95 AN XY: 83602

Gnomad AFR exome AF: 0.0249

Gnomad AMR exome AF: 0.000687

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: 0.0000326

Gnomad OTH exome AF: 0.000445

GnomAD4 exome AF: 0.000734 AC: 1027 AN: 1399492 Hom.: 18 Cov.: 31 AF XY: 0.000666 AC XY: 460 AN XY: 690246

Gnomad4 AFR exome AF: 0.0279

Gnomad4 AMR exome AF: 0.000840

Gnomad4 ASJ exome AF: 0.0000397

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000631

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000834

Gnomad4 OTH exome AF: 0.00169

GnomAD4 genome AF: 0.00704 AC: 1073 AN: 152334 Hom.: 12 Cov.: 31 AF XY: 0.00678 AC XY: 505 AN XY: 74504

Gnomad4 AFR AF: 0.0246

Gnomad4 AMR AF: 0.00248

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000103

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.00144 Hom.: 8

Bravo AF: 0.00828

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.0260 AC: 36

ESP6500EA AF: 0.000314 AC: 1

ExAC AF: 0.00272 AC: 74

Asia WGS AF: 0.00144 AC: 6 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

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

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Oct 18, 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:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 24, 2018	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. -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

May 07, 2012

Asp676Gly in Exon 15 of LOXHD1: This variant is not expected to have clinical si gnificance because it has been identified in 6.8% (5/74) of chromosomes from a p opulation in the dbSNP database (http://www.ncbi.nlm.nih.gov/projects/SNP; rs169 78578). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.75	T
BayesDel_noAF	Benign	-0.83
CADD	Benign	12
DANN	Benign	0.93
Eigen	Benign	-0.38
Eigen_PC	Benign	-0.29
FATHMM_MKL	Benign	0.34	N
LIST_S2	Benign	0.60	T;T;T
MetaRNN	Benign	0.0027	T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	0.69	N;N;N
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-0.080	N;.;.
REVEL	Benign	0.022
Sift	Benign	0.62	T;.;.
Sift4G	Benign	1.0	T;.;T
Polyphen		0.0	B;.;.
Vest4		0.13
MVP		0.061
ClinPred		0.0044	T
GERP RS		1.8
Varity_R		0.066
gMVP		0.42

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs16978578; hg19: chr18-44152069;