rs78427072

Variant names:

• chr18-46524728-C-T
• rs78427072
• NM_001384474.1:c.4720G>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.4720G>A​(p.Glu1574Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000432 in 1,551,744 control chromosomes in the GnomAD database, including 2 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 0.0023 (2 hom., cov: 33)
  • Exomes 𝑓: 0.00023 (0 hom.)
• Consequence: LOXHD1 NM_001384474.1 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: 3.17
• Publications: 4 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, PanelApp Australia, 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0116016865).
• BP6: Variant 18-46524728-C-T is Benign according to our data. Variant chr18-46524728-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 227524.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00225 (343/152342) while in subpopulation AFR AF = 0.00772 (321/41576). AF 95% confidence interval is 0.00703. There are 2 homozygotes in GnomAd4. There are 155 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.4720G>A	p.Glu1574Lys	missense	Exon 30 of 41	NP_001371403.1	A0A2R8Y7K4
	LOXHD1	NM_144612.7		c.4720G>A	p.Glu1574Lys	missense	Exon 30 of 40	NP_653213.6
	LOXHD1	NM_001145472.3		c.1387G>A	p.Glu463Lys	missense	Exon 12 of 24	NP_001138944.1	Q8IVV2-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LOXHD1	ENST00000642948.1	MANE Select	c.4720G>A	p.Glu1574Lys	missense	Exon 30 of 41	ENSP00000496347.1	A0A2R8Y7K4
	LOXHD1	ENST00000300591.11	TSL:1	c.1387G>A	p.Glu463Lys	missense	Exon 12 of 24	ENSP00000300591.6	Q8IVV2-3
	LOXHD1	ENST00000579038.6	TSL:1	c.1099G>A	p.Glu367Lys	missense	Exon 10 of 22	ENSP00000463285.1	J3QKX9

Frequencies

GnomAD3 genomes AF: 0.00225 AC: 342 AN: 152224 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.00774

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000981

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.000424 AC: 67 AN: 157908 AF XY: 0.000337

Gnomad AFR exome AF: 0.00691

Gnomad AMR exome AF: 0.000121

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000330

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000234 AC: 327 AN: 1399402 Hom.: 0 Cov.: 32 AF XY: 0.000190 AC XY: 131 AN XY: 690206

African (AFR) AF: 0.00835 AC: 264 AN: 31598

American (AMR) AF: 0.000252 AC: 9 AN: 35704

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

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

South Asian (SAS) AF: 0.0000757 AC: 6 AN: 79236

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49270

Middle Eastern (MID) AF: 0.000176 AC: 1 AN: 5698

European-Non Finnish (NFE) AF: 0.0000195 AC: 21 AN: 1078974

Other (OTH) AF: 0.000448 AC: 26 AN: 58002

GnomAD4 genome AF: 0.00225 AC: 343 AN: 152342 Hom.: 2 Cov.: 33 AF XY: 0.00208 AC XY: 155 AN XY: 74498

African (AFR) AF: 0.00772 AC: 321 AN: 41576

American (AMR) AF: 0.000980 AC: 15 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

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

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68032

Other (OTH) AF: 0.00189 AC: 4 AN: 2114

Alfa AF: 0.000998 Hom.: 1

Bravo AF: 0.00242

ESP6500AA AF: 0.00723 AC: 10

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000946 AC: 24

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	-	Inborn genetic diseases (1)
-	-	1	LOXHD1-related disorder (1)
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.68
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.31
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.075	T
Eigen	Uncertain	0.48
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.91	D
M_CAP	Benign	0.041	D
MetaRNN	Benign	0.012	T
MetaSVM	Benign	-0.40	T
PhyloP100		3.2
PrimateAI	Uncertain	0.63	T
PROVEAN	Uncertain	-3.1	D
REVEL	Uncertain	0.34
Sift	Benign	0.13	T
Sift4G	Benign	0.85	T
Polyphen		0.99	D
Vest4		0.36
MVP		0.25
ClinPred		0.044	T
GERP RS		5.0
Varity_R		0.16
gMVP		0.57
Mutation Taster		=70/30	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: rs78427072; hg19: chr18-44104691; COSMIC: COSV104613094; COSMIC: COSV104613094;