18-46483635-G-A

Variant names:

• chr18-46483635-G-A
• rs1377016
• NM_001384474.1:c.6293C>T

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.6293C>T​(p.Ala2098Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.338 in 1,551,192 control chromosomes in the GnomAD database, including 93,793 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.31 (8303 hom., cov: 31)
  • Exomes 𝑓: 0.34 (85490 hom.)
• Consequence: LOXHD1 NM_001384474.1 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 0.643
• Publications: 34 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=1.0759802E-5).
• BP6: Variant 18-46483635-G-A is Benign according to our data. Variant chr18-46483635-G-A is described in ClinVar as Benign. ClinVar VariationId is 47949.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.726 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.6293C>T	p.Ala2098Val	missense	Exon 40 of 41	NP_001371403.1	A0A2R8Y7K4
	LOXHD1	NM_144612.7		c.6107C>T	p.Ala2036Val	missense	Exon 39 of 40	NP_653213.6
	LOXHD1	NM_001145472.3		c.2960C>T	p.Ala987Val	missense	Exon 22 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.6293C>T	p.Ala2098Val	missense	Exon 40 of 41	ENSP00000496347.1	A0A2R8Y7K4
	LOXHD1	ENST00000300591.11	TSL:1	c.2960C>T	p.Ala987Val	missense	Exon 22 of 24	ENSP00000300591.6	Q8IVV2-3
	LOXHD1	ENST00000579038.6	TSL:1	c.2672C>T	p.Ala891Val	missense	Exon 20 of 22	ENSP00000463285.1	J3QKX9

Frequencies

GnomAD3 genomes AF: 0.314 AC: 47617 AN: 151722 Hom.: 8286 Cov.: 31

Gnomad AFR AF: 0.207

Gnomad AMI AF: 0.230

Gnomad AMR AF: 0.384

Gnomad ASJ AF: 0.247

Gnomad EAS AF: 0.747

Gnomad SAS AF: 0.321

Gnomad FIN AF: 0.361

Gnomad MID AF: 0.212

Gnomad NFE AF: 0.327

Gnomad OTH AF: 0.329

GnomAD2 exomes AF: 0.368 AC: 57607 AN: 156616 AF XY: 0.361

Gnomad AFR exome AF: 0.211

Gnomad AMR exome AF: 0.443

Gnomad ASJ exome AF: 0.259

Gnomad EAS exome AF: 0.742

Gnomad FIN exome AF: 0.373

Gnomad NFE exome AF: 0.326

Gnomad OTH exome AF: 0.337

GnomAD4 exome AF: 0.341 AC: 477016 AN: 1399352 Hom.: 85490 Cov.: 45 AF XY: 0.340 AC XY: 234630 AN XY: 690170

African (AFR) AF: 0.196 AC: 6193 AN: 31600

American (AMR) AF: 0.427 AC: 15242 AN: 35704

Ashkenazi Jewish (ASJ) AF: 0.265 AC: 6669 AN: 25182

East Asian (EAS) AF: 0.770 AC: 27527 AN: 35734

South Asian (SAS) AF: 0.315 AC: 24929 AN: 79234

European-Finnish (FIN) AF: 0.365 AC: 17964 AN: 49282

Middle Eastern (MID) AF: 0.240 AC: 1369 AN: 5696

European-Non Finnish (NFE) AF: 0.331 AC: 357640 AN: 1078908

Other (OTH) AF: 0.336 AC: 19483 AN: 58012

GnomAD4 genome AF: 0.314 AC: 47686 AN: 151840 Hom.: 8303 Cov.: 31 AF XY: 0.318 AC XY: 23566 AN XY: 74174

African (AFR) AF: 0.208 AC: 8606 AN: 41436

American (AMR) AF: 0.384 AC: 5868 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.247 AC: 855 AN: 3460

East Asian (EAS) AF: 0.746 AC: 3836 AN: 5142

South Asian (SAS) AF: 0.323 AC: 1541 AN: 4768

European-Finnish (FIN) AF: 0.361 AC: 3801 AN: 10540

Middle Eastern (MID) AF: 0.207 AC: 61 AN: 294

European-Non Finnish (NFE) AF: 0.327 AC: 22210 AN: 67916

Other (OTH) AF: 0.332 AC: 699 AN: 2108

Alfa AF: 0.324 Hom.: 29386

Bravo AF: 0.315

TwinsUK AF: 0.319 AC: 1181

ALSPAC AF: 0.333 AC: 1283

ExAC AF: 0.300 AC: 7619

Asia WGS AF: 0.483 AC: 1675 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	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	0.061
BayesDel_addAF	Benign	-0.71	T
BayesDel_noAF	Benign	-0.64
CADD	Benign	13
DANN	Benign	0.93
DEOGEN2	Benign	0.0087	T
Eigen	Benign	-0.72
Eigen_PC	Benign	-0.52
FATHMM_MKL	Benign	0.16	N
LIST_S2	Benign	0.036	T
MetaRNN	Benign	0.000011	T
MetaSVM	Benign	-0.95	T
PhyloP100		0.64
PrimateAI	Benign	0.45	T
PROVEAN	Benign	0.38	N
REVEL	Benign	0.063
Sift	Benign	0.54	T
Sift4G	Benign	0.50	T
Polyphen		0.0	B
Vest4		0.029
ClinPred		0.0017	T
GERP RS		3.2
Varity_R		0.036
gMVP		0.17
Mutation Taster		=100/0	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: rs1377016; hg19: chr18-44063598; COSMIC: COSV56061006;