rs367630521

Variant names:

• chr18-46560230-C-T
• rs367630521
• NM_001384474.1:c.2914G>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.2914G>A​(p.Glu972Lys) variant causes a missense change. The variant allele was found at a frequency of 0.000228 in 1,551,574 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 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 0.0012 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00012 (2 hom.)
• Consequence: LOXHD1 NM_001384474.1 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:3
• Conservation: PhyloP100: 3.90
• Publications: 0 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=0.007861972).
• BP6: Variant 18-46560230-C-T is Benign according to our data. Variant chr18-46560230-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 228822.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00122 (186/152302) while in subpopulation AFR AF = 0.00421 (175/41578). AF 95% confidence interval is 0.0037. There are 0 homozygotes in GnomAd4. There are 90 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 2 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.2914G>A	p.Glu972Lys	missense	Exon 19 of 41	NP_001371403.1	A0A2R8Y7K4
	LOXHD1	NM_144612.7		c.2914G>A	p.Glu972Lys	missense	Exon 19 of 40	NP_653213.6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LOXHD1	ENST00000642948.1	MANE Select	c.2914G>A	p.Glu972Lys	missense	Exon 19 of 41	ENSP00000496347.1	A0A2R8Y7K4
	LOXHD1	ENST00000536736.5	TSL:5	c.2914G>A	p.Glu972Lys	missense	Exon 19 of 40	ENSP00000444586.1	F5GZB4
	LOXHD1	ENST00000441551.6	TSL:5	c.2599-2741G>A		intron	N/A	ENSP00000387621.2	Q8IVV2-1

Frequencies

GnomAD3 genomes AF: 0.00122 AC: 185 AN: 152184 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00420

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000458

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00143

GnomAD2 exomes AF: 0.000309 AC: 49 AN: 158796 AF XY: 0.000203

Gnomad AFR exome AF: 0.00443

Gnomad AMR exome AF: 0.000161

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000265

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000443

GnomAD4 exome AF: 0.000119 AC: 167 AN: 1399272 Hom.: 2 Cov.: 37 AF XY: 0.0000942 AC XY: 65 AN XY: 690078

African (AFR) AF: 0.00437 AC: 138 AN: 31598

American (AMR) AF: 0.000224 AC: 8 AN: 35702

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

East Asian (EAS) AF: 0.000112 AC: 4 AN: 35738

South Asian (SAS) AF: 0.0000127 AC: 1 AN: 78940

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49392

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5696

European-Non Finnish (NFE) AF: 0.00000278 AC: 3 AN: 1078992

Other (OTH) AF: 0.000224 AC: 13 AN: 58032

GnomAD4 genome AF: 0.00122 AC: 186 AN: 152302 Hom.: 0 Cov.: 32 AF XY: 0.00121 AC XY: 90 AN XY: 74460

African (AFR) AF: 0.00421 AC: 175 AN: 41578

American (AMR) AF: 0.000457 AC: 7 AN: 15310

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

East Asian (EAS) AF: 0.000194 AC: 1 AN: 5160

South Asian (SAS) AF: 0.00 AC: 0 AN: 4804

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68032

Other (OTH) AF: 0.00142 AC: 3 AN: 2114

Alfa AF: 0.00128 Hom.: 0

Bravo AF: 0.00138

ESP6500AA AF: 0.00289 AC: 4

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000206 AC: 12

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	3	1	Autosomal recessive nonsyndromic hearing loss 77 (4)
-	1	1	not provided (2)
-	-	1	LOXHD1-related disorder (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	20
DANN	Benign	0.93
Eigen	Benign	0.036
Eigen_PC	Benign	0.064
FATHMM_MKL	Benign	0.58	D
LIST_S2	Benign	0.77	T
M_CAP	Benign	0.052	D
MetaRNN	Benign	0.0079	T
MetaSVM	Benign	-0.94	T
PhyloP100		3.9
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-0.54	N
REVEL	Benign	0.050
Sift	Benign	0.17	T
Sift4G	Benign	0.70	T
Polyphen		0.0070	B
Vest4		0.40
MVP		0.061
ClinPred		0.0096	T
GERP RS		3.1
gMVP		0.32
Mutation Taster		=87/13	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: rs367630521; hg19: chr18-44140193;