rs775871086

chr18-46509757-T-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001384474.1(LOXHD1):c.5458A>T(p.Thr1820Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000102 in 1,551,276 control chromosomes in the GnomAD database, including 1 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 0.000092 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00010 (1 hom.)
• Consequence: LOXHD1 NM_001384474.1 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:1
• Conservation: PhyloP100: 6.16

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 -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.051597178).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LOXHD1	NM_001384474.1	c.5458A>T	p.Thr1820Ser	missense_variant	35/41	ENST00000642948.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LOXHD1	ENST00000642948.1	c.5458A>T	p.Thr1820Ser	missense_variant	35/41		NM_001384474.1	P1

Frequencies

GnomAD3 genomes AF: 0.0000922 AC: 14 AN: 151842 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000328

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000297 AC: 47 AN: 158434 Hom.: 0 AF XY: 0.000324 AC XY: 27 AN XY: 83448

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000889

Gnomad ASJ exome AF: 0.00224

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000176

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000164

Gnomad OTH exome AF: 0.000224

GnomAD4 exome AF: 0.000103 AC: 144 AN: 1399316 Hom.: 1 Cov.: 31 AF XY: 0.000106 AC XY: 73 AN XY: 690158

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000868

Gnomad4 ASJ exome AF: 0.00206

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000215

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000297

Gnomad4 OTH exome AF: 0.000172

GnomAD4 genome AF: 0.0000921 AC: 14 AN: 151960 Hom.: 0 Cov.: 32 AF XY: 0.000108 AC XY: 8 AN XY: 74264

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000328

Gnomad4 ASJ AF: 0.00173

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000293 Hom.: 0

ExAC AF: 0.000223 AC: 6

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Autosomal recessive nonsyndromic hearing loss 77 Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Jun 19, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jun 26, 2017

Variant classified as Uncertain Significance - Favor Benign. The p.Thr1758Ser va riant in LOXHD1 has been previously reported by our laboratory in 1 Ashkenazi Je wish individual with hearing loss; however, a variant affecting the remaining co py of LOXHD1 was not identified. This variant has been identified in 0.25% (21/8 532) of Ashkenazi Jewish chromosomes by the genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs775871086); however, this frequency i s not high enough to rule out a pathogenic role. Computational prediction tools and conservation analysis suggest that this variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity. In s ummary, while the clinical significance of the p.Thr1758Ser variant is uncertain , available data suggest that it is more likely to be benign. -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 16, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.41
Cadd	Uncertain	24
Dann	Benign	0.93
Eigen	Uncertain	0.32
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.95	D;D;D;D;D;D;D;D;D
M_CAP	Benign	0.039	D
MetaRNN	Benign	0.052	T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.46	T
MutationTaster	Benign	0.82	D;D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-0.68	N;.;N;.;N;N;.;.;N
REVEL	Benign	0.17
Sift	Benign	0.36	T;.;T;.;T;T;.;.;T
Sift4G	Benign	0.23	T;T;T;T;D;T;.;D;.
Polyphen		0.63	.;.;.;.;P;.;.;.;.
Vest4		0.34
MutPred		0.48		.;.;.;.;Loss of helix (P = 0.0138);.;.;.;.;
MVP		0.27
ClinPred		0.076	T
GERP RS		5.5
Varity_R		0.12
gMVP		0.17

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: rs775871086; hg19: chr18-44089720;