rs189873733

Variant names:

• chr18-46477553-G-A
• rs189873733
• NM_001384474.1:c.6741C>T

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4 BP6 BS1 BS2

The NM_001384474.1(LOXHD1):​c.6741C>T​(p.Ala2247Ala) variant causes a synonymous change. The variant allele was found at a frequency of 0.00381 in 1,551,616 control chromosomes in the GnomAD database, including 18 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 0.0031 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0039 (18 hom.)
• Consequence: LOXHD1 NM_001384474.1 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:6
• Conservation: PhyloP100: 4.05
• Publications: 2 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.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.17).
• BP6: Variant 18-46477553-G-A is Benign according to our data. Variant chr18-46477553-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 178390.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00305 (465/152346) while in subpopulation NFE AF = 0.00463 (315/68024). AF 95% confidence interval is 0.00421. There are 0 homozygotes in GnomAd4. There are 215 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 18 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LOXHD1	NM_001384474.1	MANE Select	c.6741C>T	p.Ala2247Ala	synonymous	Exon 41 of 41	NP_001371403.1
	LOXHD1	NM_144612.7		c.6555C>T	p.Ala2185Ala	synonymous	Exon 40 of 40	NP_653213.6
	LOXHD1	NM_001145473.3		c.1458C>T	p.Ala486Ala	synonymous	Exon 9 of 9	NP_001138945.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LOXHD1	ENST00000642948.1	MANE Select	c.6741C>T	p.Ala2247Ala	synonymous	Exon 41 of 41	ENSP00000496347.1
	LOXHD1	ENST00000398686.8	TSL:1	c.1458C>T	p.Ala486Ala	synonymous	Exon 9 of 9	ENSP00000381676.4
	LOXHD1	ENST00000300591.11	TSL:1	c.3307+101C>T		intron	N/A	ENSP00000300591.6

Frequencies

GnomAD3 genomes AF: 0.00306 AC: 466 AN: 152228 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00111

Gnomad AMI AF: 0.00329

Gnomad AMR AF: 0.00412

Gnomad ASJ AF: 0.00346

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.00122

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00463

Gnomad OTH AF: 0.00334

GnomAD2 exomes AF: 0.00286 AC: 441 AN: 154122 AF XY: 0.00291

Gnomad AFR exome AF: 0.00153

Gnomad AMR exome AF: 0.00215

Gnomad ASJ exome AF: 0.00377

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00162

Gnomad NFE exome AF: 0.00453

Gnomad OTH exome AF: 0.00508

GnomAD4 exome AF: 0.00389 AC: 5447 AN: 1399270 Hom.: 18 Cov.: 31 AF XY: 0.00380 AC XY: 2621 AN XY: 690140

African (AFR) AF: 0.00111 AC: 35 AN: 31598

American (AMR) AF: 0.00266 AC: 95 AN: 35704

Ashkenazi Jewish (ASJ) AF: 0.00373 AC: 94 AN: 25182

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

South Asian (SAS) AF: 0.00120 AC: 95 AN: 79232

European-Finnish (FIN) AF: 0.00205 AC: 101 AN: 49218

Middle Eastern (MID) AF: 0.00426 AC: 24 AN: 5628

European-Non Finnish (NFE) AF: 0.00447 AC: 4824 AN: 1078976

Other (OTH) AF: 0.00307 AC: 178 AN: 57994

GnomAD4 genome AF: 0.00305 AC: 465 AN: 152346 Hom.: 0 Cov.: 33 AF XY: 0.00289 AC XY: 215 AN XY: 74508

African (AFR) AF: 0.00111 AC: 46 AN: 41578

American (AMR) AF: 0.00411 AC: 63 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00346 AC: 12 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00124 AC: 6 AN: 4832

European-Finnish (FIN) AF: 0.00122 AC: 13 AN: 10628

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

European-Non Finnish (NFE) AF: 0.00463 AC: 315 AN: 68024

Other (OTH) AF: 0.00331 AC: 7 AN: 2116

Alfa AF: 0.00291 Hom.: 1

Bravo AF: 0.00290

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	2	-	Autosomal recessive nonsyndromic hearing loss 77 (2)
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.17
CADD	Benign	7.3
DANN	Benign	0.75
PhyloP100		4.1
Mutation Taster		=86/14	polymorphism

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: rs189873733; hg19: chr18-44057516;