rs369039902

Variant names:

• chr18-46577733-G-A
• rs369039902
• NM_001384474.1:c.1944C>T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BS1 BS2

The NM_001384474.1(LOXHD1):​c.1944C>T​(p.Ser648Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000474 in 1,551,448 control chromosomes in the GnomAD database, including 6 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 0.00033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00049 (6 hom.)
• Consequence: LOXHD1 NM_001384474.1 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:3
• Conservation: PhyloP100: -1.83

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.71).
• BP6: Variant 18-46577733-G-A is Benign according to our data. Variant chr18-46577733-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 287384.We mark this variant Likely_benign, oryginal submissions are: {Benign=2, Uncertain_significance=2}.
• BP7: Synonymous conserved (PhyloP=-1.83 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. gnomad4_exome allele frequency = 0.000489 (684/1399194) while in subpopulation SAS AF= 0.00389 (308/79234). AF 95% confidence interval is 0.00353. There are 6 homozygotes in gnomad4_exome. There are 439 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LOXHD1	NM_001384474.1	c.1944C>T	p.Ser648Ser	synonymous_variant	Exon 14 of 41	ENST00000642948.1	NP_001371403.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LOXHD1	ENST00000642948.1	c.1944C>T	p.Ser648Ser	synonymous_variant	Exon 14 of 41		NM_001384474.1	ENSP00000496347.1
LOXHD1	ENST00000536736.5	c.1944C>T	p.Ser648Ser	synonymous_variant	Exon 14 of 40	5		ENSP00000444586.1
LOXHD1	ENST00000441551.6	c.1944C>T	p.Ser648Ser	synonymous_variant	Exon 14 of 39	5		ENSP00000387621.2
LOXHD1	ENST00000335730.6	n.1257C>T		non_coding_transcript_exon_variant	Exon 7 of 27	2

Frequencies

GnomAD3 genomes AF: 0.000335 AC: 51 AN: 152136 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00332

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000456

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000818 AC: 129 AN: 157766 Hom.: 2 AF XY: 0.00103 AC XY: 86 AN XY: 83092

Gnomad AFR exome AF: 0.000115

Gnomad AMR exome AF: 0.000162

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000177

Gnomad SAS exome AF: 0.00360

Gnomad FIN exome AF: 0.0000593

Gnomad NFE exome AF: 0.000595

Gnomad OTH exome AF: 0.000675

GnomAD4 exome AF: 0.000489 AC: 684 AN: 1399194 Hom.: 6 Cov.: 31 AF XY: 0.000636 AC XY: 439 AN XY: 690056

Gnomad4 AFR exome AF: 0.0000316

Gnomad4 AMR exome AF: 0.000280

Gnomad4 ASJ exome AF: 0.0000397

Gnomad4 EAS exome AF: 0.000168

Gnomad4 SAS exome AF: 0.00389

Gnomad4 FIN exome AF: 0.0000203

Gnomad4 NFE exome AF: 0.000292

Gnomad4 OTH exome AF: 0.000466

GnomAD4 genome AF: 0.000335 AC: 51 AN: 152254 Hom.: 0 Cov.: 32 AF XY: 0.000403 AC XY: 30 AN XY: 74428

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00333

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000456

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000396 Hom.: 0

Bravo AF: 0.000302

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

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

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Jun 18, 2020

Natera, Inc.

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided Uncertain:1 Benign:1

May 17, 2016

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 16, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

Jul 21, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

p.Ser648Ser in Exon 14 of LOXHD1: This variant is not expected to have clinical significance because it does not alter an amino acid residue, is not located wit hin the splice consensus sequence, and has been identified in 0.5 (37/7902) of S outh Asian chromosomes including two homozygotes by the Exome Aggregation Consor tium (ExAC, http://exac.broadinstitute.org; dbSNP rs369039902). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.71
CADD	Benign	1.4
DANN	Benign	0.58

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs369039902; hg19: chr18-44157696; COSMIC: COSV100191386;