chr18-46579731-C-T

Position:

• chr18-46579731-C-T

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.1708G>A​(p.Asp570Asn) variant causes a missense change. The variant allele was found at a frequency of 0.000659 in 1,551,798 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0033 (1 hom., cov: 33)
  • Exomes 𝑓: 0.00037 (2 hom.)
• Consequence: LOXHD1 NM_001384474.1 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4
• Conservation: PhyloP100: 4.41

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.010522395).
• BP6: Variant 18-46579731-C-T is Benign according to our data. Variant chr18-46579731-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 47919.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=1, Benign=1}.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00331 (504/152312) while in subpopulation AFR AF= 0.0109 (455/41568). AF 95% confidence interval is 0.0101. There are 1 homozygotes in gnomad4. There are 245 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LOXHD1	NM_001384474.1	c.1708G>A	p.Asp570Asn	missense_variant	13/41	ENST00000642948.1	NP_001371403.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LOXHD1	ENST00000642948.1	c.1708G>A	p.Asp570Asn	missense_variant	13/41		NM_001384474.1	ENSP00000496347.1
LOXHD1	ENST00000536736.5	c.1708G>A	p.Asp570Asn	missense_variant	13/40	5		ENSP00000444586.1
LOXHD1	ENST00000441551.6	c.1708G>A	p.Asp570Asn	missense_variant	13/39	5		ENSP00000387621.2
LOXHD1	ENST00000335730.6	n.1021G>A		non_coding_transcript_exon_variant	6/27	2

Frequencies

GnomAD3 genomes AF: 0.00332 AC: 506 AN: 152194 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.0110

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00183

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: 0.000118

Gnomad OTH AF: 0.00575

GnomAD3 exomes AF: 0.000724 AC: 115 AN: 158870 Hom.: 0 AF XY: 0.000574 AC XY: 48 AN XY: 83582

Gnomad AFR exome AF: 0.0107

Gnomad AMR exome AF: 0.000606

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: 0.0000652

Gnomad OTH exome AF: 0.000446

GnomAD4 exome AF: 0.000370 AC: 518 AN: 1399486 Hom.: 2 Cov.: 31 AF XY: 0.000310 AC XY: 214 AN XY: 690248

Gnomad4 AFR exome AF: 0.0117

Gnomad4 AMR exome AF: 0.000728

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000631

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000602

Gnomad4 OTH exome AF: 0.000827

GnomAD4 genome AF: 0.00331 AC: 504 AN: 152312 Hom.: 1 Cov.: 33 AF XY: 0.00329 AC XY: 245 AN XY: 74480

Gnomad4 AFR AF: 0.0109

Gnomad4 AMR AF: 0.00183

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000118

Gnomad4 OTH AF: 0.00569

Alfa AF: 0.00185 Hom.: 0

Bravo AF: 0.00400

ESP6500AA AF: 0.00867 AC: 12

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00104 AC: 29

Asia WGS AF: 0.000866 AC: 3 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

Likely benign, no assertion criteria provided	clinical testing	Natera, Inc.	Jan 02, 2020	- -
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

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 18, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Dec 21, 2017

p.Asp570Asn variant in exon 13 of LOXHD1: This variant is not expected to have c linical significance because it has been identified in 193/16434 (1.2%) African American chromosomes by the genome Aggregation Database (gnomAD, http://gnomad.b roadinstitute.org/; dbSNP rs140437150). ACMG/AMP criteria applied: BA1. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.36
CADD	Uncertain	23
DANN	Uncertain	0.99
Eigen	Uncertain	0.36
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.89	D;D;D
MetaRNN	Benign	0.011	T;T;T
MetaSVM	Benign	-0.50	T
PrimateAI	Uncertain	0.62	T
PROVEAN	Uncertain	-3.4	D;.;.
REVEL	Benign	0.21
Sift	Benign	0.14	T;.;.
Sift4G	Benign	0.14	T;.;T
Polyphen		0.58	P;.;.
Vest4		0.28
MVP		0.23
ClinPred		0.068	T
GERP RS		4.3
Varity_R		0.19
gMVP		0.63

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: rs140437150; hg19: chr18-44159694; COSMIC: COSV59660958;