18-46538251-C-T

Variant names:

• chr18-46538251-C-T
• rs1555673818
• NM_001384474.1:c.4000G>A

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP4

The NM_001384474.1(LOXHD1):​c.4000G>A​(p.Asp1334Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000786 in 1,399,126 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000079 (0 hom.)
• Consequence: LOXHD1 NM_001384474.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.41
• Publications: 0 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 -1 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.2831117).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LOXHD1	NM_001384474.1	c.4000G>A	p.Asp1334Asn	missense_variant	Exon 26 of 41	ENST00000642948.1	NP_001371403.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LOXHD1	ENST00000642948.1	c.4000G>A	p.Asp1334Asn	missense_variant	Exon 26 of 41		NM_001384474.1	ENSP00000496347.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000786 AC: 11 AN: 1399126 Hom.: 0 Cov.: 31 AF XY: 0.00000435 AC XY: 3 AN XY: 690032

African (AFR) AF: 0.0000316 AC: 1 AN: 31596

American (AMR) AF: 0.0000560 AC: 2 AN: 35698

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

East Asian (EAS) AF: 0.0000280 AC: 1 AN: 35724

South Asian (SAS) AF: 0.0000379 AC: 3 AN: 79234

European-Finnish (FIN) AF: 0.0000203 AC: 1 AN: 49280

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5696

European-Non Finnish (NFE) AF: 0.00000278 AC: 3 AN: 1078722

Other (OTH) AF: 0.00 AC: 0 AN: 57994

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

May 16, 2017

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Asp1334Asn variant in LOXHD1 has not been previously reported in individua ls with hearing loss or in large population studies. Computational prediction to ols and conservation analyses suggest that this variant may not impact the prote in, though this information is not predictive enough to rule out pathogenicity. In summary, the clinical significance of the p.Asp1334Asn variant is uncertain. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.74
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.018	.;.;T;.;.;.
Eigen	Uncertain	0.30
Eigen_PC	Uncertain	0.34
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Uncertain	0.92	D;D;D;D;D;D
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.28	T;T;T;T;T;T
MetaSVM	Benign	-0.99	T
PhyloP100		2.4
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-2.2	.;N;.;N;.;.
REVEL	Benign	0.18
Sift	Benign	0.70	.;T;.;T;.;.
Sift4G	Benign	0.33	T;T;T;T;.;T
Polyphen		1.0	.;.;.;D;.;.
Vest4		0.13
MutPred		0.58		.;.;.;Loss of loop (P = 0.0374);Loss of loop (P = 0.0374);.;
MVP		0.076
ClinPred		0.93	D
GERP RS		5.5
Varity_R		0.12
gMVP		0.49
Mutation Taster		=73/27	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: rs1555673818; hg19: chr18-44118214;