18-46488987-C-T

Variant names:

• chr18-46488987-C-T
• rs79045813
• NM_001384474.1:c.6034G>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.6034G>A​(p.Glu2012Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000592 in 1,551,684 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict 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. E2012E) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0033 (2 hom., cov: 32)
  • Exomes 𝑓: 0.00029 (3 hom.)
• Consequence: LOXHD1 NM_001384474.1 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4
• Conservation: PhyloP100: 3.44
• Publications: 3 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: G2P, PanelApp Australia, Labcorp Genetics (formerly Invitae), Ambry Genetics
• 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=0.008004129).
• BP6: Variant 18-46488987-C-T is Benign according to our data. Variant chr18-46488987-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 178393.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00334 (509/152334) while in subpopulation AFR AF = 0.0119 (494/41588). AF 95% confidence interval is 0.011. There are 2 homozygotes in GnomAd4. There are 248 alleles in the male GnomAd4 subpopulation. Median coverage is 32. 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LOXHD1	NM_001384474.1	MANE Select	c.6034G>A	p.Glu2012Lys	missense	Exon 38 of 41	NP_001371403.1
	LOXHD1	NM_144612.7		c.5848G>A	p.Glu1950Lys	missense	Exon 37 of 40	NP_653213.6
	LOXHD1	NM_001145472.3		c.2701G>A	p.Glu901Lys	missense	Exon 20 of 24	NP_001138944.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LOXHD1	ENST00000642948.1	MANE Select	c.6034G>A	p.Glu2012Lys	missense	Exon 38 of 41	ENSP00000496347.1
	LOXHD1	ENST00000300591.11	TSL:1	c.2701G>A	p.Glu901Lys	missense	Exon 20 of 24	ENSP00000300591.6
	LOXHD1	ENST00000579038.6	TSL:1	c.2413G>A	p.Glu805Lys	missense	Exon 18 of 22	ENSP00000463285.1

Frequencies

GnomAD3 genomes AF: 0.00334 AC: 509 AN: 152216 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.0119

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000720

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: 0.0000147

Gnomad OTH AF: 0.00144

GnomAD2 exomes AF: 0.000703 AC: 110 AN: 156502 AF XY: 0.000579

Gnomad AFR exome AF: 0.0114

Gnomad AMR exome AF: 0.000567

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000331

Gnomad OTH exome AF: 0.000684

GnomAD4 exome AF: 0.000292 AC: 409 AN: 1399350 Hom.: 3 Cov.: 31 AF XY: 0.000227 AC XY: 157 AN XY: 690170

African (AFR) AF: 0.0110 AC: 349 AN: 31598

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

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25180

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 79234

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49266

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5698

European-Non Finnish (NFE) AF: 0.00000463 AC: 5 AN: 1078926

Other (OTH) AF: 0.000552 AC: 32 AN: 58006

GnomAD4 genome AF: 0.00334 AC: 509 AN: 152334 Hom.: 2 Cov.: 32 AF XY: 0.00333 AC XY: 248 AN XY: 74484

African (AFR) AF: 0.0119 AC: 494 AN: 41588

American (AMR) AF: 0.000719 AC: 11 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

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

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68026

Other (OTH) AF: 0.00142 AC: 3 AN: 2112

Alfa AF: 0.00133 Hom.: 1

Bravo AF: 0.00391

ESP6500AA AF: 0.00939 AC: 13

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000911 AC: 24

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.088
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	17
DANN	Benign	0.95
DEOGEN2	Benign	0.0050	T
Eigen	Benign	0.057
Eigen_PC	Benign	0.12
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.95	D
MetaRNN	Benign	0.0080	T
MetaSVM	Benign	-1.1	T
PhyloP100		3.4
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-0.83	N
REVEL	Benign	0.15
Sift	Benign	0.55	T
Sift4G	Benign	0.38	T
Polyphen		0.99	D
Vest4		0.21
MVP		0.067
ClinPred		0.030	T
GERP RS		5.6
Varity_R		0.17
gMVP		0.32
Mutation Taster		=67/33	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs79045813; hg19: chr18-44068950;