rs187587197

Variant names:

• chr18-46529181-C-T
• rs187587197
• NM_001384474.1:c.4526G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 1P and 13B. PP3 BP4_Strong BP6 BS1 BS2

The NM_001384474.1(LOXHD1):​c.4526G>A​(p.Gly1509Glu) variant causes a missense change. The variant allele was found at a frequency of 0.0063 in 1,551,526 control chromosomes in the GnomAD database, including 107 homozygotes. In-silico tool predicts 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. G1509R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0070 (19 hom., cov: 32)
  • Exomes 𝑓: 0.0062 (88 hom.)
• Consequence: LOXHD1 NM_001384474.1 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:9
• Conservation: PhyloP100: 6.07
• Publications: 15 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 -12 ACMG points.

• PP3: Multiple lines of computational evidence support a deleterious effect 6: Cadd, Eigen, FATHMM_MKL, PROVEAN, REVEL, REVEL [when BayesDel_addAF, max_spliceai, MetaRNN, MutationTaster was below the threshold]
• BP4: Computational evidence support a benign effect (MetaRNN=0.008006483).
• BP6: Variant 18-46529181-C-T is Benign according to our data. Variant chr18-46529181-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 178612.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00697 (1061/152134) while in subpopulation NFE AF = 0.0056 (381/68006). AF 95% confidence interval is 0.00514. There are 19 homozygotes in GnomAd4. There are 645 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 19 AR,AD 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.4526G>A	p.Gly1509Glu	missense	Exon 29 of 41	NP_001371403.1	A0A2R8Y7K4
	LOXHD1	NM_144612.7		c.4526G>A	p.Gly1509Glu	missense	Exon 29 of 40	NP_653213.6
	LOXHD1	NM_001145472.3		c.1193G>A	p.Gly398Glu	missense	Exon 11 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.4526G>A	p.Gly1509Glu	missense	Exon 29 of 41	ENSP00000496347.1	A0A2R8Y7K4
	LOXHD1	ENST00000300591.11	TSL:1	c.1193G>A	p.Gly398Glu	missense	Exon 11 of 24	ENSP00000300591.6	Q8IVV2-3
	LOXHD1	ENST00000579038.6	TSL:1	c.905G>A	p.Gly302Glu	missense	Exon 9 of 22	ENSP00000463285.1	J3QKX9

Frequencies

GnomAD3 genomes AF: 0.00698 AC: 1061 AN: 152016 Hom.: 19 Cov.: 32

Gnomad AFR AF: 0.000967

Gnomad AMI AF: 0.0219

Gnomad AMR AF: 0.000590

Gnomad ASJ AF: 0.00259

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.0560

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00560

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.00783 AC: 1242 AN: 158560 AF XY: 0.00735

Gnomad AFR exome AF: 0.00137

Gnomad AMR exome AF: 0.000647

Gnomad ASJ exome AF: 0.00176

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0519

Gnomad NFE exome AF: 0.00460

Gnomad OTH exome AF: 0.00514

GnomAD4 exome AF: 0.00622 AC: 8711 AN: 1399392 Hom.: 88 Cov.: 32 AF XY: 0.00609 AC XY: 4202 AN XY: 690196

African (AFR) AF: 0.000791 AC: 25 AN: 31594

American (AMR) AF: 0.000728 AC: 26 AN: 35702

Ashkenazi Jewish (ASJ) AF: 0.00171 AC: 43 AN: 25182

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

South Asian (SAS) AF: 0.000808 AC: 64 AN: 79234

European-Finnish (FIN) AF: 0.0528 AC: 2600 AN: 49288

Middle Eastern (MID) AF: 0.000702 AC: 4 AN: 5696

European-Non Finnish (NFE) AF: 0.00529 AC: 5705 AN: 1078956

Other (OTH) AF: 0.00421 AC: 244 AN: 58002

GnomAD4 genome AF: 0.00697 AC: 1061 AN: 152134 Hom.: 19 Cov.: 32 AF XY: 0.00867 AC XY: 645 AN XY: 74354

African (AFR) AF: 0.000964 AC: 40 AN: 41504

American (AMR) AF: 0.000589 AC: 9 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.00259 AC: 9 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5162

South Asian (SAS) AF: 0.00104 AC: 5 AN: 4810

European-Finnish (FIN) AF: 0.0560 AC: 593 AN: 10586

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

European-Non Finnish (NFE) AF: 0.00560 AC: 381 AN: 68006

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

Alfa AF: 0.00459 Hom.: 11

Bravo AF: 0.00271

TwinsUK AF: 0.00405 AC: 15

ALSPAC AF: 0.00545 AC: 21

ESP6500AA AF: 0.00145 AC: 2

ESP6500EA AF: 0.00440 AC: 14

ExAC AF: 0.00569 AC: 152

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	3	Autosomal recessive nonsyndromic hearing loss 77 (4)
-	-	4	not provided (4)
-	-	2	not specified (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.49
BayesDel_addAF	Benign	-0.084	T
BayesDel_noAF	Uncertain	0.12
CADD	Pathogenic	27
DANN	Uncertain	0.98
DEOGEN2	Benign	0.19	T
Eigen	Pathogenic	0.88
Eigen_PC	Pathogenic	0.80
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	D
MetaRNN	Benign	0.0080	T
MetaSVM	Benign	-0.39	T
PhyloP100		6.1
PrimateAI	Uncertain	0.67	T
PROVEAN	Pathogenic	-6.1	D
REVEL	Pathogenic	0.82
Sift	Uncertain	0.0050	D
Sift4G	Uncertain	0.0070	D
Polyphen		1.0	D
Vest4		0.74
MVP		0.22
ClinPred		0.034	T
GERP RS		5.1
Varity_R		0.52
gMVP		0.61
Mutation Taster		=25/75	disease causing

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: rs187587197; hg19: chr18-44109144; COSMIC: COSV106427991; COSMIC: COSV106427991;