rs59128481

Variant names:

• chr18-46518116-C-T
• rs59128481
• NM_001384474.1:c.5399+13G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001384474.1(LOXHD1):​c.5399+13G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0923 in 1,550,968 control chromosomes in the GnomAD database, including 7,153 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.072 (526 hom., cov: 32)
  • Exomes 𝑓: 0.095 (6627 hom.)
• Consequence: LOXHD1 NM_001384474.1 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -1.53
• Publications: 6 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: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 18-46518116-C-T is Benign according to our data. Variant chr18-46518116-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 47944.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0992 is higher than 0.05.

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.5399+13G>A		intron	N/A	NP_001371403.1	A0A2R8Y7K4
	LOXHD1	NM_144612.7		c.5213+13G>A		intron	N/A	NP_653213.6
	LOXHD1	NM_001145472.3		c.2066+13G>A		intron	N/A	NP_001138944.1	Q8IVV2-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LOXHD1	ENST00000642948.1	MANE Select	c.5399+13G>A		intron	N/A	ENSP00000496347.1	A0A2R8Y7K4
	LOXHD1	ENST00000300591.11	TSL:1	c.2066+13G>A		intron	N/A	ENSP00000300591.6	Q8IVV2-3
	LOXHD1	ENST00000579038.6	TSL:1	c.1778+13G>A		intron	N/A	ENSP00000463285.1	J3QKX9

Frequencies

GnomAD3 genomes AF: 0.0719 AC: 10928 AN: 152070 Hom.: 525 Cov.: 32

Gnomad AFR AF: 0.0225

Gnomad AMI AF: 0.255

Gnomad AMR AF: 0.0804

Gnomad ASJ AF: 0.0925

Gnomad EAS AF: 0.0581

Gnomad SAS AF: 0.0710

Gnomad FIN AF: 0.0444

Gnomad MID AF: 0.0696

Gnomad NFE AF: 0.101

Gnomad OTH AF: 0.0961

GnomAD2 exomes AF: 0.0771 AC: 12082 AN: 156710 AF XY: 0.0795

Gnomad AFR exome AF: 0.0224

Gnomad AMR exome AF: 0.0546

Gnomad ASJ exome AF: 0.0981

Gnomad EAS exome AF: 0.0600

Gnomad FIN exome AF: 0.0454

Gnomad NFE exome AF: 0.102

Gnomad OTH exome AF: 0.0882

GnomAD4 exome AF: 0.0946 AC: 132292 AN: 1398780 Hom.: 6627 Cov.: 33 AF XY: 0.0944 AC XY: 65155 AN XY: 689902

African (AFR) AF: 0.0176 AC: 555 AN: 31588

American (AMR) AF: 0.0563 AC: 2009 AN: 35698

Ashkenazi Jewish (ASJ) AF: 0.0966 AC: 2432 AN: 25178

East Asian (EAS) AF: 0.0388 AC: 1387 AN: 35736

South Asian (SAS) AF: 0.0785 AC: 6221 AN: 79206

European-Finnish (FIN) AF: 0.0488 AC: 2404 AN: 49274

Middle Eastern (MID) AF: 0.0742 AC: 391 AN: 5272

European-Non Finnish (NFE) AF: 0.103 AC: 111584 AN: 1078876

Other (OTH) AF: 0.0916 AC: 5309 AN: 57952

GnomAD4 genome AF: 0.0718 AC: 10923 AN: 152188 Hom.: 526 Cov.: 32 AF XY: 0.0696 AC XY: 5182 AN XY: 74402

African (AFR) AF: 0.0224 AC: 932 AN: 41536

American (AMR) AF: 0.0802 AC: 1227 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.0925 AC: 321 AN: 3472

East Asian (EAS) AF: 0.0575 AC: 297 AN: 5166

South Asian (SAS) AF: 0.0709 AC: 341 AN: 4812

European-Finnish (FIN) AF: 0.0444 AC: 471 AN: 10610

Middle Eastern (MID) AF: 0.0714 AC: 21 AN: 294

European-Non Finnish (NFE) AF: 0.101 AC: 6880 AN: 67984

Other (OTH) AF: 0.0951 AC: 201 AN: 2114

Alfa AF: 0.0864 Hom.: 127

Bravo AF: 0.0722

Asia WGS AF: 0.0580 AC: 202 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	Autosomal recessive nonsyndromic hearing loss 77 (2)
-	-	2	not specified (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	1.7
DANN	Benign	0.53
PhyloP100		-1.5
Mutation Taster		=100/0	polymorphism (auto)

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: rs59128481; hg19: chr18-44098079;