rs10163657

Variant names:

• chr18-46601264-C-T
• rs10163657
• NM_001384474.1:c.1087G>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.1087G>A​(p.Val363Ile) variant causes a missense change. The variant allele was found at a frequency of 0.075 in 1,551,622 control chromosomes in the GnomAD database, including 4,723 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/19 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. V363V) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.059 (322 hom., cov: 32)
  • Exomes 𝑓: 0.077 (4401 hom.)
• Consequence: LOXHD1 NM_001384474.1 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 5.14
• Publications: 18 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=0.0015088618).
• BP6: Variant 18-46601264-C-T is Benign according to our data. Variant chr18-46601264-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 47916.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0842 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.1087G>A	p.Val363Ile	missense	Exon 8 of 41	NP_001371403.1	A0A2R8Y7K4
	LOXHD1	NM_144612.7		c.1087G>A	p.Val363Ile	missense	Exon 8 of 40	NP_653213.6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LOXHD1	ENST00000642948.1	MANE Select	c.1087G>A	p.Val363Ile	missense	Exon 8 of 41	ENSP00000496347.1	A0A2R8Y7K4
	LOXHD1	ENST00000536736.5	TSL:5	c.1087G>A	p.Val363Ile	missense	Exon 8 of 40	ENSP00000444586.1	F5GZB4
	LOXHD1	ENST00000441551.6	TSL:5	c.1087G>A	p.Val363Ile	missense	Exon 8 of 39	ENSP00000387621.2	Q8IVV2-1

Frequencies

GnomAD3 genomes AF: 0.0590 AC: 8968 AN: 152116 Hom.: 321 Cov.: 32

Gnomad AFR AF: 0.0195

Gnomad AMI AF: 0.137

Gnomad AMR AF: 0.0579

Gnomad ASJ AF: 0.0576

Gnomad EAS AF: 0.0329

Gnomad SAS AF: 0.0444

Gnomad FIN AF: 0.0517

Gnomad MID AF: 0.0665

Gnomad NFE AF: 0.0860

Gnomad OTH AF: 0.0695

GnomAD2 exomes AF: 0.0612 AC: 9685 AN: 158248 AF XY: 0.0618

Gnomad AFR exome AF: 0.0189

Gnomad AMR exome AF: 0.0393

Gnomad ASJ exome AF: 0.0625

Gnomad EAS exome AF: 0.0326

Gnomad FIN exome AF: 0.0521

Gnomad NFE exome AF: 0.0869

Gnomad OTH exome AF: 0.0695

GnomAD4 exome AF: 0.0767 AC: 107390 AN: 1399388 Hom.: 4401 Cov.: 32 AF XY: 0.0764 AC XY: 52715 AN XY: 690200

African (AFR) AF: 0.0183 AC: 579 AN: 31598

American (AMR) AF: 0.0409 AC: 1462 AN: 35704

Ashkenazi Jewish (ASJ) AF: 0.0648 AC: 1631 AN: 25182

East Asian (EAS) AF: 0.0180 AC: 645 AN: 35738

South Asian (SAS) AF: 0.0519 AC: 4116 AN: 79236

European-Finnish (FIN) AF: 0.0537 AC: 2645 AN: 49276

Middle Eastern (MID) AF: 0.0730 AC: 416 AN: 5696

European-Non Finnish (NFE) AF: 0.0853 AC: 92006 AN: 1078952

Other (OTH) AF: 0.0671 AC: 3890 AN: 58006

GnomAD4 genome AF: 0.0589 AC: 8968 AN: 152234 Hom.: 322 Cov.: 32 AF XY: 0.0564 AC XY: 4198 AN XY: 74428

African (AFR) AF: 0.0195 AC: 809 AN: 41552

American (AMR) AF: 0.0578 AC: 884 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0576 AC: 200 AN: 3472

East Asian (EAS) AF: 0.0330 AC: 171 AN: 5184

South Asian (SAS) AF: 0.0449 AC: 216 AN: 4814

European-Finnish (FIN) AF: 0.0517 AC: 548 AN: 10600

Middle Eastern (MID) AF: 0.0680 AC: 20 AN: 294

European-Non Finnish (NFE) AF: 0.0860 AC: 5850 AN: 68000

Other (OTH) AF: 0.0688 AC: 145 AN: 2108

Alfa AF: 0.0777 Hom.: 2229

Bravo AF: 0.0566

TwinsUK AF: 0.0820 AC: 304

ALSPAC AF: 0.0859 AC: 331

ESP6500AA AF: 0.0181 AC: 25

ESP6500EA AF: 0.0902 AC: 287

ExAC AF: 0.0565 AC: 1436

Asia WGS AF: 0.0380 AC: 132 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.052
BayesDel_addAF	Benign	-0.61	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	18
DANN	Uncertain	0.99
Eigen	Benign	-0.68
Eigen_PC	Benign	-0.37
FATHMM_MKL	Benign	0.091	N
LIST_S2	Benign	0.55	T
MetaRNN	Benign	0.0015	T
MetaSVM	Benign	-1.1	T
PhyloP100		5.1
PrimateAI	Uncertain	0.71	T
PROVEAN	Benign	0.64	N
REVEL	Benign	0.087
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.23
ClinPred		0.019	T
GERP RS		5.6
Varity_R		0.086
gMVP		0.14
Mutation Taster		=94/6	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: rs10163657; hg19: chr18-44181227; COSMIC: COSV59665656;