chr18-46649190-C-A

Position:

• chr18-46649190-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001384474.1(LOXHD1):​c.210G>T​(p.Glu70Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000121 in 1,399,458 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: LOXHD1 NM_001384474.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2
• Conservation: PhyloP100: 0.0360

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.1475879).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LOXHD1	NM_001384474.1	c.210G>T	p.Glu70Asp	missense_variant	2/41	ENST00000642948.1	NP_001371403.1
LOXHD1	NM_144612.7	c.210G>T	p.Glu70Asp	missense_variant	2/40		NP_653213.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LOXHD1	ENST00000642948.1	c.210G>T	p.Glu70Asp	missense_variant	2/41		NM_001384474.1	ENSP00000496347	P1
LOXHD1	ENST00000536736.5	c.210G>T	p.Glu70Asp	missense_variant	2/40	5		ENSP00000444586
LOXHD1	ENST00000441551.6	c.210G>T	p.Glu70Asp	missense_variant	2/39	5		ENSP00000387621

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.0000765 AC: 12 AN: 156866 Hom.: 0 AF XY: 0.0000602 AC XY: 5 AN XY: 83082

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000486

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000121 AC: 17 AN: 1399458 Hom.: 0 Cov.: 31 AF XY: 0.00000869 AC XY: 6 AN XY: 690234

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000448

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000172

GnomAD4 genome Cov.: 33

Bravo AF: 0.0000113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Oct 10, 2015

Variant classified as Uncertain Significance - Favor Benign. The p.Glu70Asp vari ant in LOXHD1 has not been previously reported in individuals with hearing loss and was absent from large population studies. The glutamic acid (Glu) at amino a cid position 70 is conserved through mammals; however, several fish species have an aspartic acid (Asp) at this position, raising the possibility that this vari ant could be tolerated. Additional computational prediction tools and conservati on analysis suggest the variant may not impact the protein, though this informat ion is not predictive enough to rule out pathogenicity. In summary, while the cl inical significance of the p.Glu70Asp variant is uncertain, the conservation dat a suggest that it is more likely to be benign. -

Autosomal recessive nonsyndromic hearing loss 77 Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Natera, Inc.

Oct 28, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.26
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	17
DANN	Benign	0.94
Eigen	Benign	-0.051
Eigen_PC	Benign	0.034
FATHMM_MKL	Benign	0.67	D
LIST_S2	Benign	0.83	T;T;T
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.15	T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	0.70	N;N
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-1.2	N;.;.
REVEL	Benign	0.087
Sift	Benign	0.38	T;.;.
Sift4G	Benign	0.23	T;.;T
Polyphen		0.035	B;.;.
Vest4		0.16
MutPred		0.58		Gain of relative solvent accessibility (P = 0.09);Gain of relative solvent accessibility (P = 0.09);Gain of relative solvent accessibility (P = 0.09);
MVP		0.14
ClinPred		0.048	T
GERP RS		3.5
Varity_R		0.096
gMVP		0.44

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

Publications

LitVar

Other links and lift over

dbSNP: rs876657859; hg19: chr18-44229153;