rs61733519

Variant names:

• chr18-46505914-G-T
• rs61733519
• NM_001384474.1:c.5802C>A

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001384474.1(LOXHD1):​c.5802C>A​(p.Asn1934Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00399 in 1,551,990 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0031 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0041 (12 hom.)
• Consequence: LOXHD1 NM_001384474.1 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:7
• Conservation: PhyloP100: 2.61
• Publications: 11 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0058615804).
• BP6: Variant 18-46505914-G-T is Benign according to our data. Variant chr18-46505914-G-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 47946.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00308 (469/152316) while in subpopulation AMR AF = 0.00562 (86/15312). AF 95% confidence interval is 0.00466. There are 1 homozygotes in GnomAd4. There are 214 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 12 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.5802C>A	p.Asn1934Lys	missense	Exon 37 of 41	NP_001371403.1
	LOXHD1	NM_144612.7		c.5616C>A	p.Asn1872Lys	missense	Exon 36 of 40	NP_653213.6
	LOXHD1	NM_001145472.3		c.2469C>A	p.Asn823Lys	missense	Exon 19 of 24	NP_001138944.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LOXHD1	ENST00000642948.1	MANE Select	c.5802C>A	p.Asn1934Lys	missense	Exon 37 of 41	ENSP00000496347.1
	LOXHD1	ENST00000300591.11	TSL:1	c.2469C>A	p.Asn823Lys	missense	Exon 19 of 24	ENSP00000300591.6
	LOXHD1	ENST00000579038.6	TSL:1	c.2181C>A	p.Asn727Lys	missense	Exon 17 of 22	ENSP00000463285.1

Frequencies

GnomAD3 genomes AF: 0.00308 AC: 469 AN: 152198 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000893

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00562

Gnomad ASJ AF: 0.000864

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00245

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00450

Gnomad OTH AF: 0.00526

GnomAD2 exomes AF: 0.00278 AC: 439 AN: 157646 AF XY: 0.00244

Gnomad AFR exome AF: 0.000739

Gnomad AMR exome AF: 0.00441

Gnomad ASJ exome AF: 0.000587

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00248

Gnomad NFE exome AF: 0.00431

Gnomad OTH exome AF: 0.00292

GnomAD4 exome AF: 0.00409 AC: 5718 AN: 1399674 Hom.: 12 Cov.: 31 AF XY: 0.00385 AC XY: 2659 AN XY: 690322

African (AFR) AF: 0.00108 AC: 34 AN: 31598

American (AMR) AF: 0.00398 AC: 142 AN: 35704

Ashkenazi Jewish (ASJ) AF: 0.000357 AC: 9 AN: 25182

East Asian (EAS) AF: 0.00 AC: 0 AN: 35738

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

European-Finnish (FIN) AF: 0.00190 AC: 94 AN: 49390

Middle Eastern (MID) AF: 0.000526 AC: 3 AN: 5700

European-Non Finnish (NFE) AF: 0.00484 AC: 5226 AN: 1079030

Other (OTH) AF: 0.00358 AC: 208 AN: 58096

GnomAD4 genome AF: 0.00308 AC: 469 AN: 152316 Hom.: 1 Cov.: 32 AF XY: 0.00287 AC XY: 214 AN XY: 74486

African (AFR) AF: 0.000890 AC: 37 AN: 41568

American (AMR) AF: 0.00562 AC: 86 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.000864 AC: 3 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00 AC: 0 AN: 4818

European-Finnish (FIN) AF: 0.00245 AC: 26 AN: 10624

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

European-Non Finnish (NFE) AF: 0.00450 AC: 306 AN: 68032

Other (OTH) AF: 0.00521 AC: 11 AN: 2112

Alfa AF: 0.00376 Hom.: 4

Bravo AF: 0.00315

TwinsUK AF: 0.00566 AC: 21

ALSPAC AF: 0.00467 AC: 18

ESP6500AA AF: 0.00145 AC: 2

ESP6500EA AF: 0.00691 AC: 22

ExAC AF: 0.00183 AC: 48

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
-	2	2	Autosomal recessive nonsyndromic hearing loss 77 (4)
-	1	3	not provided (4)
-	1	-	Inborn genetic diseases (1)
-	-	1	LOXHD1-related disorder (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	22
DANN	Benign	0.95
DEOGEN2	Benign	0.019	T
Eigen	Benign	-0.25
Eigen_PC	Benign	-0.078
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Uncertain	0.93	D
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.0059	T
MetaSVM	Benign	-0.97	T
PhyloP100		2.6
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-2.1	N
REVEL	Benign	0.050
Sift	Benign	0.052	T
Sift4G	Benign	0.60	T
Polyphen		0.0040	B
Vest4		0.21
MutPred		0.52		Gain of ubiquitination at N1872 (P = 0.0192)
MVP		0.21
ClinPred		0.027	T
GERP RS		2.5
Varity_R		0.085
gMVP		0.45
Mutation Taster		=97/3	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: rs61733519; hg19: chr18-44085877;