NM_001384474.1:c.2473G>A

Variant names:

• chr18-46563190-C-T
• rs36086089
• NM_001384474.1:c.2473G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001384474.1(LOXHD1):​c.2473G>A​(p.Val825Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0852 in 1,522,664 control chromosomes in the GnomAD database, including 6,175 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. V825V) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.095 (803 hom., cov: 32)
  • Exomes 𝑓: 0.084 (5372 hom.)
• Consequence: LOXHD1 NM_001384474.1 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 0.775
• Publications: 14 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0016309619).
• BP6: Variant 18-46563190-C-T is Benign according to our data. Variant chr18-46563190-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 47928.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.133 is higher than 0.05.

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.2473G>A	p.Val825Met	missense	Exon 18 of 41	NP_001371403.1	A0A2R8Y7K4
	LOXHD1	NM_144612.7		c.2473G>A	p.Val825Met	missense	Exon 18 of 40	NP_653213.6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LOXHD1	ENST00000642948.1	MANE Select	c.2473G>A	p.Val825Met	missense	Exon 18 of 41	ENSP00000496347.1	A0A2R8Y7K4
	LOXHD1	ENST00000536736.5	TSL:5	c.2473G>A	p.Val825Met	missense	Exon 18 of 40	ENSP00000444586.1	F5GZB4
	LOXHD1	ENST00000441551.6	TSL:5	c.2473G>A	p.Val825Met	missense	Exon 18 of 39	ENSP00000387621.2	Q8IVV2-1

Frequencies

GnomAD3 genomes AF: 0.0947 AC: 14394 AN: 152064 Hom.: 800 Cov.: 32

Gnomad AFR AF: 0.136

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0662

Gnomad ASJ AF: 0.118

Gnomad EAS AF: 0.00308

Gnomad SAS AF: 0.125

Gnomad FIN AF: 0.106

Gnomad MID AF: 0.142

Gnomad NFE AF: 0.0788

Gnomad OTH AF: 0.0952

GnomAD2 exomes AF: 0.0867 AC: 13685 AN: 157836 AF XY: 0.0918

Gnomad AFR exome AF: 0.138

Gnomad AMR exome AF: 0.0516

Gnomad ASJ exome AF: 0.122

Gnomad EAS exome AF: 0.00319

Gnomad FIN exome AF: 0.0949

Gnomad NFE exome AF: 0.0802

Gnomad OTH exome AF: 0.0952

GnomAD4 exome AF: 0.0841 AC: 115253 AN: 1370480 Hom.: 5372 Cov.: 31 AF XY: 0.0860 AC XY: 57601 AN XY: 670068

African (AFR) AF: 0.138 AC: 4299 AN: 31212

American (AMR) AF: 0.0530 AC: 1872 AN: 35318

Ashkenazi Jewish (ASJ) AF: 0.119 AC: 2960 AN: 24818

East Asian (EAS) AF: 0.00200 AC: 70 AN: 34966

South Asian (SAS) AF: 0.141 AC: 10999 AN: 78026

European-Finnish (FIN) AF: 0.0954 AC: 4659 AN: 48828

Middle Eastern (MID) AF: 0.149 AC: 833 AN: 5604

European-Non Finnish (NFE) AF: 0.0799 AC: 84344 AN: 1055186

Other (OTH) AF: 0.0923 AC: 5217 AN: 56522

GnomAD4 genome AF: 0.0947 AC: 14413 AN: 152184 Hom.: 803 Cov.: 32 AF XY: 0.0947 AC XY: 7043 AN XY: 74398

African (AFR) AF: 0.136 AC: 5655 AN: 41490

American (AMR) AF: 0.0661 AC: 1010 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.118 AC: 410 AN: 3468

East Asian (EAS) AF: 0.00308 AC: 16 AN: 5190

South Asian (SAS) AF: 0.125 AC: 604 AN: 4824

European-Finnish (FIN) AF: 0.106 AC: 1118 AN: 10594

Middle Eastern (MID) AF: 0.143 AC: 42 AN: 294

European-Non Finnish (NFE) AF: 0.0788 AC: 5360 AN: 68012

Other (OTH) AF: 0.0938 AC: 198 AN: 2112

Alfa AF: 0.0837 Hom.: 1223

Bravo AF: 0.0933

TwinsUK AF: 0.0704 AC: 261

ALSPAC AF: 0.0778 AC: 300

ESP6500AA AF: 0.140 AC: 194

ESP6500EA AF: 0.0867 AC: 276

ExAC AF: 0.101 AC: 2588

Asia WGS AF: 0.0780 AC: 272 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	19
DANN	Benign	0.97
Eigen	Benign	-0.28
Eigen_PC	Benign	-0.19
FATHMM_MKL	Benign	0.44	N
LIST_S2	Benign	0.81	T
MetaRNN	Benign	0.0016	T
MetaSVM	Benign	-1.0	T
PhyloP100		0.78
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-1.7	N
REVEL	Benign	0.048
Sift	Benign	0.070	T
Sift4G	Benign	0.17	T
Polyphen		0.19	B
Vest4		0.099
ClinPred		0.0056	T
GERP RS		4.0
Varity_R		0.042
gMVP		0.34
Mutation Taster		=69/31	polymorphism (auto)

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: rs36086089; hg19: chr18-44143153;