rs201576880

Positions:

• chr18-46546960-T-C

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP6

The NM_001384474.1(LOXHD1):​c.3449A>G​(p.Gln1150Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000209 in 1,551,742 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. Q1150Q) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00083 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00014 (0 hom.)
• Consequence: LOXHD1 NM_001384474.1 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4
• Conservation: PhyloP100: 1.81

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 Likely_benign. Variant got -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.0050894916).
• BP6: Variant 18-46546960-T-C is Benign according to our data. Variant chr18-46546960-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 504610.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=4}. Variant chr18-46546960-T-C is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LOXHD1	NM_001384474.1	c.3449A>G	p.Gln1150Arg	missense_variant	22/41	ENST00000642948.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LOXHD1	ENST00000642948.1	c.3449A>G	p.Gln1150Arg	missense_variant	22/41		NM_001384474.1	P1

Frequencies

GnomAD3 genomes AF: 0.000834 AC: 127 AN: 152230 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00265

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000851

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: 0.0000441

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000221 AC: 35 AN: 158338 Hom.: 0 AF XY: 0.000144 AC XY: 12 AN XY: 83414

Gnomad AFR exome AF: 0.00288

Gnomad AMR exome AF: 0.000323

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000164

Gnomad OTH exome AF: 0.000224

GnomAD4 exome AF: 0.000141 AC: 198 AN: 1399394 Hom.: 0 Cov.: 34 AF XY: 0.000136 AC XY: 94 AN XY: 690204

Gnomad4 AFR exome AF: 0.00294

Gnomad4 AMR exome AF: 0.000336

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000126

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000565

Gnomad4 OTH exome AF: 0.000483

GnomAD4 genome AF: 0.000827 AC: 126 AN: 152348 Hom.: 0 Cov.: 33 AF XY: 0.000859 AC XY: 64 AN XY: 74504

Gnomad4 AFR AF: 0.00262

Gnomad4 AMR AF: 0.000850

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000534 Hom.: 0

Bravo AF: 0.00113

ESP6500AA AF: 0.00289 AC: 4

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000365 AC: 10

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 25, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2022	LOXHD1: BP4, BS1:Supporting -

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 14, 2023

The c.3449A>G (p.Q1150R) alteration is located in exon 22 (coding exon 22) of the LOXHD1 gene. This alteration results from a A to G substitution at nucleotide position 3449, causing the glutamine (Q) at amino acid position 1150 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jun 04, 2016

p.Gln1150Arg in exon 22 of LOXHD1: This variant is not expected to have clinical significance because it has been identified in 0.36% (10/2758) of African chrom osomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org ; dbSNP rs201576880). In addition, computational tools and conservation analysis does not suggest an impact to the protein. -

LOXHD1-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 04, 2023

This variant is classified as likely 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
AlphaMissense	Benign	0.087
BayesDel_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-0.67
CADD	Benign	13
DANN	Benign	0.27
Eigen	Benign	-0.78
Eigen_PC	Benign	-0.77
FATHMM_MKL	Benign	0.70	D
LIST_S2	Benign	0.73	T;T;T;T;T
M_CAP	Benign	0.0060	T
MetaRNN	Benign	0.0051	T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	N;N;N;N;N;N;N
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.61	N;.;N;.;.
REVEL	Benign	0.060
Sift	Benign	0.20	T;.;T;.;.
Sift4G	Uncertain	0.031	D;D;D;.;T
Polyphen		0.74	.;.;P;.;.
Vest4		0.091
MVP		0.030
ClinPred		0.022	T
GERP RS		1.1
Varity_R		0.022
gMVP		0.44

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs201576880; hg19: chr18-44126923;