rs115658952

Variant names:

• chr18-46566387-G-A
• rs115658952
• NM_001384474.1:c.2307C>T

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6 BP7 BS1 BS2

The NM_001384474.1(LOXHD1):​c.2307C>T​(p.Ser769Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000471 in 1,551,540 control chromosomes in the GnomAD database, including 2 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0025 (2 hom., cov: 33)
  • Exomes 𝑓: 0.00025 (0 hom.)
• Consequence: LOXHD1 NM_001384474.1 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: -0.536
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• autosomal recessive nonsyndromic hearing loss 77

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, PanelApp Australia, Labcorp Genetics (formerly Invitae), Ambry Genetics
• nonsyndromic genetic hearing loss

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• hearing loss, autosomal recessive

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• Fuchs' endothelial dystrophy

  Inheritance: AD Classification: LIMITED Submitted by: Illumina

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• BP6: Variant 18-46566387-G-A is Benign according to our data. Variant chr18-46566387-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 226713.
• BP7: Synonymous conserved (PhyloP=-0.536 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00248 (378/152332) while in subpopulation AFR AF = 0.00852 (354/41572). AF 95% confidence interval is 0.00778. There are 2 homozygotes in GnomAd4. There are 162 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001384474.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LOXHD1	NM_001384474.1	MANE Select	c.2307C>T	p.Ser769Ser	synonymous	Exon 17 of 41	NP_001371403.1
	LOXHD1	NM_144612.7		c.2307C>T	p.Ser769Ser	synonymous	Exon 17 of 40	NP_653213.6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LOXHD1	ENST00000642948.1	MANE Select	c.2307C>T	p.Ser769Ser	synonymous	Exon 17 of 41	ENSP00000496347.1
	LOXHD1	ENST00000536736.5	TSL:5	c.2307C>T	p.Ser769Ser	synonymous	Exon 17 of 40	ENSP00000444586.1
	LOXHD1	ENST00000441551.6	TSL:5	c.2307C>T	p.Ser769Ser	synonymous	Exon 17 of 39	ENSP00000387621.2

Frequencies

GnomAD3 genomes AF: 0.00248 AC: 377 AN: 152214 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.00854

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000982

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00287

GnomAD2 exomes AF: 0.000455 AC: 72 AN: 158264 AF XY: 0.000372

Gnomad AFR exome AF: 0.00749

Gnomad AMR exome AF: 0.000162

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000328

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000252 AC: 353 AN: 1399208 Hom.: 0 Cov.: 31 AF XY: 0.000213 AC XY: 147 AN XY: 690106

African (AFR) AF: 0.00886 AC: 280 AN: 31594

American (AMR) AF: 0.000224 AC: 8 AN: 35706

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25182

East Asian (EAS) AF: 0.0000280 AC: 1 AN: 35738

South Asian (SAS) AF: 0.0000252 AC: 2 AN: 79236

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49062

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5700

European-Non Finnish (NFE) AF: 0.0000334 AC: 36 AN: 1078974

Other (OTH) AF: 0.000448 AC: 26 AN: 58016

GnomAD4 genome AF: 0.00248 AC: 378 AN: 152332 Hom.: 2 Cov.: 33 AF XY: 0.00217 AC XY: 162 AN XY: 74502

African (AFR) AF: 0.00852 AC: 354 AN: 41572

American (AMR) AF: 0.000980 AC: 15 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5184

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68038

Other (OTH) AF: 0.00284 AC: 6 AN: 2114

Alfa AF: 0.00139 Hom.: 0

Bravo AF: 0.00262

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	-	Autosomal recessive nonsyndromic hearing loss 77 (1)
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.45
CADD	Benign	0.96
DANN	Benign	0.75
PhyloP100		-0.54

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

Other links and lift over

dbSNP: rs115658952; hg19: chr18-44146350;