rs876657499

Positions:

• chr18-46610865-T-G

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM2 BP4_Moderate BP6

The NM_001384474.1(LOXHD1):​c.670A>C​(p.Ile224Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000572 in 1,399,476 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 Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000057 (0 hom.)
• Consequence: LOXHD1 NM_001384474.1 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 5.03

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 Likely_benign. Variant got -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.22131595).
• BP6: Variant 18-46610865-T-G is Benign according to our data. Variant chr18-46610865-T-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 227531.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LOXHD1	NM_001384474.1	c.670A>C	p.Ile224Leu	missense_variant	6/41	ENST00000642948.1	NP_001371403.1
LOXHD1	NM_144612.7	c.670A>C	p.Ile224Leu	missense_variant	6/40		NP_653213.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LOXHD1	ENST00000642948.1	c.670A>C	p.Ile224Leu	missense_variant	6/41		NM_001384474.1	ENSP00000496347.1
LOXHD1	ENST00000536736.5	c.670A>C	p.Ile224Leu	missense_variant	6/40	5		ENSP00000444586.1
LOXHD1	ENST00000441551.6	c.670A>C	p.Ile224Leu	missense_variant	6/39	5		ENSP00000387621.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000127 AC: 2 AN: 157154 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 83148

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

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: 0.0000328

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000572 AC: 8 AN: 1399476 Hom.: 0 Cov.: 30 AF XY: 0.00000580 AC XY: 4 AN XY: 690234

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 0.00000741

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.0000113

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 27, 2022

The c.670A>C (p.I224L) alteration is located in exon 6 (coding exon 6) of the LOXHD1 gene. This alteration results from a A to C substitution at nucleotide position 670, causing the isoleucine (I) at amino acid position 224 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jul 20, 2015

p.Ile224Leu in exon 6 of LOXHD1: This variant is not expected to have clinical s ignificance because the isoleucine (Ile) residue at position 224 is not conserve d through species, with 4 mammals (rabbit, pika, alpaca, and Bactrian camel) hav ing a leucine (Leu) at this position. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.084
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	16
DANN	Benign	0.90
Eigen	Benign	-0.77
Eigen_PC	Benign	-0.60
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.48	T;T;T
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.22	T;T;T
MetaSVM	Benign	-1.0	T
PrimateAI	Benign	0.24	T
PROVEAN	Benign	0.16	N;.;.
REVEL	Benign	0.14
Sift	Benign	0.10	T;.;.
Sift4G	Uncertain	0.027	D;.;T
Polyphen		0.0	B;.;.
Vest4		0.25
MutPred		0.42		Gain of disorder (P = 0.0994);Gain of disorder (P = 0.0994);Gain of disorder (P = 0.0994);
MVP		0.055
ClinPred		0.21	T
GERP RS		3.1
Varity_R		0.092
gMVP		0.16

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: rs876657499; hg19: chr18-44190828;