chr18-46518255-A-C

Variant names:

• chr18-46518255-A-C
• rs727503139
• NM_001384474.1:c.5273T>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001384474.1(LOXHD1):​c.5273T>G​(p.Val1758Gly) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V1758F) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: LOXHD1 NM_001384474.1 missense, splice_region
• Scores: Splicing: ADA: 0.001938
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.85
• 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.012496382).

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.5273T>G	p.Val1758Gly	missense splice_region	Exon 34 of 41	NP_001371403.1
	LOXHD1	NM_144612.7		c.5087T>G	p.Val1696Gly	missense splice_region	Exon 33 of 40	NP_653213.6
	LOXHD1	NM_001145472.3		c.1940T>G	p.Val647Gly	missense splice_region	Exon 16 of 24	NP_001138944.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LOXHD1	ENST00000642948.1	MANE Select	c.5273T>G	p.Val1758Gly	missense splice_region	Exon 34 of 41	ENSP00000496347.1
	LOXHD1	ENST00000300591.11	TSL:1	c.1940T>G	p.Val647Gly	missense splice_region	Exon 16 of 24	ENSP00000300591.6
	LOXHD1	ENST00000579038.6	TSL:1	c.1652T>G	p.Val551Gly	missense splice_region	Exon 14 of 22	ENSP00000463285.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.000412 AC: 65 AN: 157592 AF XY: 0.000301

Gnomad AFR exome AF: 0.00341

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.000236

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000297

Gnomad NFE exome AF: 0.000446

Gnomad OTH exome AF: 0.000448

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 7.15e-7 AC: 1 AN: 1398976 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 689960

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 31598

American (AMR) AF: 0.00 AC: 0 AN: 35696

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25168

East Asian (EAS) AF: 0.00 AC: 0 AN: 35730

South Asian (SAS) AF: 0.00 AC: 0 AN: 79232

European-Finnish (FIN) AF: 0.0000203 AC: 1 AN: 49238

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5694

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1078636

Other (OTH) AF: 0.00 AC: 0 AN: 57984

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ExAC AF: 0.00381 AC: 102

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.41
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.0
CADD	Uncertain	25
DANN	Benign	0.90
DEOGEN2	Benign	0.094	T
Eigen	Benign	0.11
Eigen_PC	Benign	0.080
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.64	T
MetaRNN	Benign	0.0097	T
MetaSVM	Uncertain	-0.11	T
PhyloP100		5.8
PrimateAI	Uncertain	0.50	T
PROVEAN	Uncertain	-3.6	D
REVEL	Benign	0.23
Sift	Benign	0.045	D
Sift4G	Uncertain	0.0020	D
Polyphen		0.94	P
Vest4		0.36
MutPred		0.65		Loss of sheet (P = 0.0054)
MVP		0.48
ClinPred		0.13	T
GERP RS		2.5
Varity_R		0.13
gMVP		0.78

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0019
dbscSNV1_RF	Benign	0.082
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: rs727503139; hg19: chr18-44098218;