18-46522163-G-A

Variant names:

• chr18-46522163-G-A
• rs201060702
• NM_001384474.1:c.5023C>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.5023C>T​(p.Arg1675Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000985 in 1,551,604 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1675H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0015 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00093 (5 hom.)
• Consequence: LOXHD1 NM_001384474.1 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:7
• Conservation: PhyloP100: 1.05
• 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.00919342).
• BP6: Variant 18-46522163-G-A is Benign according to our data. Variant chr18-46522163-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 178395.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00151 (230/152220) while in subpopulation AMR AF = 0.00673 (103/15296). AF 95% confidence interval is 0.00568. There are 1 homozygotes in GnomAd4. There are 126 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 5 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.5023C>T	p.Arg1675Cys	missense	Exon 32 of 41	NP_001371403.1	A0A2R8Y7K4
	LOXHD1	NM_144612.7		c.5023C>T	p.Arg1675Cys	missense	Exon 32 of 40	NP_653213.6
	LOXHD1	NM_001145472.3		c.1690C>T	p.Arg564Cys	missense	Exon 14 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.5023C>T	p.Arg1675Cys	missense	Exon 32 of 41	ENSP00000496347.1	A0A2R8Y7K4
	LOXHD1	ENST00000300591.11	TSL:1	c.1690C>T	p.Arg564Cys	missense	Exon 14 of 24	ENSP00000300591.6	Q8IVV2-3
	LOXHD1	ENST00000579038.6	TSL:1	c.1402C>T	p.Arg468Cys	missense	Exon 12 of 22	ENSP00000463285.1	J3QKX9

Frequencies

GnomAD3 genomes AF: 0.00151 AC: 230 AN: 152102 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000314

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00674

Gnomad ASJ AF: 0.00490

Gnomad EAS AF: 0.000579

Gnomad SAS AF: 0.000832

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00107

Gnomad OTH AF: 0.00670

GnomAD2 exomes AF: 0.00153 AC: 243 AN: 158452 AF XY: 0.00161

Gnomad AFR exome AF: 0.000115

Gnomad AMR exome AF: 0.00444

Gnomad ASJ exome AF: 0.00424

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000592

Gnomad NFE exome AF: 0.000901

Gnomad OTH exome AF: 0.00403

GnomAD4 exome AF: 0.000928 AC: 1298 AN: 1399384 Hom.: 5 Cov.: 31 AF XY: 0.00100 AC XY: 690 AN XY: 690192

African (AFR) AF: 0.000222 AC: 7 AN: 31598

American (AMR) AF: 0.00389 AC: 139 AN: 35704

Ashkenazi Jewish (ASJ) AF: 0.00349 AC: 88 AN: 25182

East Asian (EAS) AF: 0.0000560 AC: 2 AN: 35738

South Asian (SAS) AF: 0.00101 AC: 80 AN: 79232

European-Finnish (FIN) AF: 0.0000203 AC: 1 AN: 49272

Middle Eastern (MID) AF: 0.0133 AC: 76 AN: 5698

European-Non Finnish (NFE) AF: 0.000740 AC: 798 AN: 1078950

Other (OTH) AF: 0.00184 AC: 107 AN: 58010

GnomAD4 genome AF: 0.00151 AC: 230 AN: 152220 Hom.: 1 Cov.: 32 AF XY: 0.00169 AC XY: 126 AN XY: 74426

African (AFR) AF: 0.000313 AC: 13 AN: 41534

American (AMR) AF: 0.00673 AC: 103 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00490 AC: 17 AN: 3472

East Asian (EAS) AF: 0.000580 AC: 3 AN: 5170

South Asian (SAS) AF: 0.000833 AC: 4 AN: 4804

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.00107 AC: 73 AN: 68012

Other (OTH) AF: 0.00663 AC: 14 AN: 2112

Alfa AF: 0.00138 Hom.: 2

Bravo AF: 0.00145

TwinsUK AF: 0.00135 AC: 5

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00126 AC: 4

ExAC AF: 0.00124 AC: 32

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
-	-	3	not provided (3)
-	1	1	Autosomal recessive nonsyndromic hearing loss 77 (2)
-	-	1	LOXHD1-related disorder (1)
-	-	1	not specified (1)
-	-	1	VATER association (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.060
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	19
DANN	Benign	0.89
DEOGEN2	Benign	0.057	T
Eigen	Benign	-0.48
Eigen_PC	Benign	-0.41
FATHMM_MKL	Benign	0.55	D
LIST_S2	Benign	0.83	T
M_CAP	Benign	0.057	D
MetaRNN	Benign	0.0092	T
MetaSVM	Benign	-0.64	T
PhyloP100		1.0
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-0.39	N
REVEL	Benign	0.069
Sift	Benign	0.096	T
Sift4G	Uncertain	0.057	T
Polyphen		0.035	B
Vest4		0.14
MVP		0.31
ClinPred		0.015	T
GERP RS		2.6
Varity_R		0.081
gMVP		0.53
Mutation Taster		=95/5	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs201060702; hg19: chr18-44102126; COSMIC: COSV106095989; COSMIC: COSV106095989;