18-46566430-C-A

Variant names:

• chr18-46566430-C-A
• rs188517529
• NM_001384474.1:c.2264G>T

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.2264G>T​(p.Gly755Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000433 in 1,550,428 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. G755G) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0026 (4 hom., cov: 33)
  • Exomes 𝑓: 0.00020 (0 hom.)
• Consequence: LOXHD1 NM_001384474.1 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:6
• Conservation: PhyloP100: 7.80
• Publications: 1 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.019063205).
• BP6: Variant 18-46566430-C-A is Benign according to our data. Variant chr18-46566430-C-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 163920.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00259 (394/152308) while in subpopulation AFR AF = 0.00921 (383/41564). AF 95% confidence interval is 0.00845. There are 4 homozygotes in GnomAd4. There are 189 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 4 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.2264G>T	p.Gly755Val	missense	Exon 17 of 41	NP_001371403.1	A0A2R8Y7K4
	LOXHD1	NM_144612.7		c.2264G>T	p.Gly755Val	missense	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.2264G>T	p.Gly755Val	missense	Exon 17 of 41	ENSP00000496347.1	A0A2R8Y7K4
	LOXHD1	ENST00000536736.5	TSL:5	c.2264G>T	p.Gly755Val	missense	Exon 17 of 40	ENSP00000444586.1	F5GZB4
	LOXHD1	ENST00000441551.6	TSL:5	c.2264G>T	p.Gly755Val	missense	Exon 17 of 39	ENSP00000387621.2	Q8IVV2-1

Frequencies

GnomAD3 genomes AF: 0.00259 AC: 394 AN: 152190 Hom.: 4 Cov.: 33

Gnomad AFR AF: 0.00924

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000458

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: 0.00

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.000522 AC: 82 AN: 157202 AF XY: 0.000337

Gnomad AFR exome AF: 0.00762

Gnomad AMR exome AF: 0.000566

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000225

GnomAD4 exome AF: 0.000199 AC: 278 AN: 1398120 Hom.: 0 Cov.: 31 AF XY: 0.000158 AC XY: 109 AN XY: 689620

African (AFR) AF: 0.00687 AC: 217 AN: 31598

American (AMR) AF: 0.000644 AC: 23 AN: 35704

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 35736

South Asian (SAS) AF: 0.0000126 AC: 1 AN: 79232

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48034

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

European-Non Finnish (NFE) AF: 0.0000158 AC: 17 AN: 1078934

Other (OTH) AF: 0.000328 AC: 19 AN: 58002

GnomAD4 genome AF: 0.00259 AC: 394 AN: 152308 Hom.: 4 Cov.: 33 AF XY: 0.00254 AC XY: 189 AN XY: 74480

African (AFR) AF: 0.00921 AC: 383 AN: 41564

American (AMR) AF: 0.000457 AC: 7 AN: 15304

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

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68024

Other (OTH) AF: 0.00189 AC: 4 AN: 2112

Alfa AF: 0.00101 Hom.: 0

Bravo AF: 0.00261

ESP6500AA AF: 0.00506 AC: 7

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000995 AC: 26

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	2	not specified (2)
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Uncertain	0.017	T
BayesDel_noAF	Pathogenic	0.26
CADD	Uncertain	24
DANN	Benign	0.97
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.93	D
M_CAP	Pathogenic	0.37	D
MetaRNN	Benign	0.019	T
MetaSVM	Uncertain	0.38	D
PhyloP100		7.8
PrimateAI	Uncertain	0.64	T
PROVEAN	Pathogenic	-7.5	D
REVEL	Uncertain	0.56
Sift	Uncertain	0.0060	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.97
MVP		0.39
ClinPred		0.080	T
GERP RS		4.8
Varity_R		0.55
gMVP		0.85
Mutation Taster		=56/44	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs188517529; hg19: chr18-44146393;