rs140042576

Variant names:

• chr18-46524520-C-T
• rs140042576
• NM_001384474.1:c.4822G>A

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS1

The NM_001384474.1(LOXHD1):​c.4822G>A​(p.Val1608Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000369 in 1,551,754 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V1608A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0020 (1 hom., cov: 33)
  • Exomes 𝑓: 0.00019 (0 hom.)
• Consequence: LOXHD1 NM_001384474.1 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1 B:6
• Conservation: PhyloP100: -0.991
• Publications: 2 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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0042520165).
• BP6: Variant 18-46524520-C-T is Benign according to our data. Variant chr18-46524520-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 163902.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.002 (305/152340) while in subpopulation AFR AF = 0.00714 (297/41580). AF 95% confidence interval is 0.00648. There are 1 homozygotes in GnomAd4. There are 135 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

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.4822G>A	p.Val1608Ile	missense	Exon 31 of 41	NP_001371403.1	A0A2R8Y7K4
	LOXHD1	NM_144612.7		c.4822G>A	p.Val1608Ile	missense	Exon 31 of 40	NP_653213.6
	LOXHD1	NM_001145472.3		c.1489G>A	p.Val497Ile	missense	Exon 13 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.4822G>A	p.Val1608Ile	missense	Exon 31 of 41	ENSP00000496347.1	A0A2R8Y7K4
	LOXHD1	ENST00000300591.11	TSL:1	c.1489G>A	p.Val497Ile	missense	Exon 13 of 24	ENSP00000300591.6	Q8IVV2-3
	LOXHD1	ENST00000579038.6	TSL:1	c.1201G>A	p.Val401Ile	missense	Exon 11 of 22	ENSP00000463285.1	J3QKX9

Frequencies

GnomAD3 genomes AF: 0.00196 AC: 299 AN: 152222 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.00702

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

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: 0.0000294

Gnomad OTH AF: 0.000955

GnomAD2 exomes AF: 0.000588 AC: 93 AN: 158170 AF XY: 0.000420

Gnomad AFR exome AF: 0.00967

Gnomad AMR exome AF: 0.000283

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000224

GnomAD4 exome AF: 0.000192 AC: 268 AN: 1399414 Hom.: 0 Cov.: 32 AF XY: 0.000185 AC XY: 128 AN XY: 690216

African (AFR) AF: 0.00709 AC: 224 AN: 31598

American (AMR) AF: 0.000308 AC: 11 AN: 35704

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

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

South Asian (SAS) AF: 0.0000631 AC: 5 AN: 79236

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49280

Middle Eastern (MID) AF: 0.000176 AC: 1 AN: 5698

European-Non Finnish (NFE) AF: 0.00000185 AC: 2 AN: 1078976

Other (OTH) AF: 0.000431 AC: 25 AN: 58002

GnomAD4 genome AF: 0.00200 AC: 305 AN: 152340 Hom.: 1 Cov.: 33 AF XY: 0.00181 AC XY: 135 AN XY: 74494

African (AFR) AF: 0.00714 AC: 297 AN: 41580

American (AMR) AF: 0.000261 AC: 4 AN: 15300

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

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

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68034

Other (OTH) AF: 0.000945 AC: 2 AN: 2116

Alfa AF: 0.00248 Hom.: 0

Bravo AF: 0.00250

ESP6500AA AF: 0.00361 AC: 5

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000936 AC: 24

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.064
BayesDel_addAF	Benign	-0.71	T
BayesDel_noAF	Benign	-0.79
CADD	Benign	0.056
DANN	Benign	0.80
DEOGEN2	Benign	0.0022	T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.017	N
LIST_S2	Benign	0.75	T
M_CAP	Benign	0.0080	T
MetaRNN	Benign	0.0043	T
MetaSVM	Benign	-0.99	T
PhyloP100		-0.99
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.10	N
REVEL	Benign	0.0070
Sift	Benign	0.48	T
Sift4G	Benign	0.21	T
Polyphen		0.034	B
Vest4		0.042
MVP		0.014
ClinPred		0.0050	T
GERP RS		-4.5
Varity_R		0.023
gMVP		0.13
Mutation Taster		=98/2	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: rs140042576; hg19: chr18-44104483;