rs142931455

Variant names:

• chr18-46477188-C-T
• rs142931455
• ENST00000300591.11:c.3340G>A

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001145472.3(LOXHD1):​c.3340G>A​(p.Gly1114Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00136 in 720,570 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/17 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: 𝑓 0.0011 (3 hom., cov: 33)
  • Exomes 𝑓: 0.0014 (5 hom.)
• Consequence: LOXHD1 NM_001145472.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:5
• Conservation: PhyloP100: 0.00800
• Publications: 5 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0057053566).
• BP6: Variant 18-46477188-C-T is Benign according to our data. Variant chr18-46477188-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 178389.
• BS1: Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.00142 (808/568254) while in subpopulation MID AF = 0.00931 (38/4080). AF 95% confidence interval is 0.00698. There are 5 homozygotes in GnomAdExome4. There are 431 alleles in the male GnomAdExome4 subpopulation. Median coverage is 4. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 3 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001145472.3. 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_001145472.3		c.3340G>A	p.Gly1114Arg	missense	Exon 24 of 24	NP_001138944.1	Q8IVV2-3
	LOXHD1	NM_001308013.2		c.*30G>A		3_prime_UTR	Exon 22 of 22	NP_001294942.1	J3QKX9
	LOXHD1	NM_001173129.2		c.*30G>A		3_prime_UTR	Exon 10 of 10	NP_001166600.1	Q8IVV2-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LOXHD1	ENST00000300591.11	TSL:1	c.3340G>A	p.Gly1114Arg	missense	Exon 24 of 24	ENSP00000300591.6	Q8IVV2-3
	LOXHD1	ENST00000579038.6	TSL:1	c.*30G>A		3_prime_UTR	Exon 22 of 22	ENSP00000463285.1	J3QKX9
	LOXHD1	ENST00000398705.7	TSL:2	c.*30G>A		3_prime_UTR	Exon 10 of 10	ENSP00000381692.2	Q8IVV2-4

Frequencies

GnomAD3 genomes AF: 0.00113 AC: 172 AN: 152198 Hom.: 3 Cov.: 33

Gnomad AFR AF: 0.000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00111

Gnomad ASJ AF: 0.0156

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.000941

Gnomad OTH AF: 0.00526

GnomAD2 exomes AF: 0.00154 AC: 241 AN: 156552 AF XY: 0.00134

Gnomad AFR exome AF: 0.000505

Gnomad AMR exome AF: 0.00138

Gnomad ASJ exome AF: 0.0147

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000892

Gnomad OTH exome AF: 0.00387

GnomAD4 exome AF: 0.00142 AC: 808 AN: 568254 Hom.: 5 Cov.: 4 AF XY: 0.00141 AC XY: 431 AN XY: 306484

African (AFR) AF: 0.000821 AC: 13 AN: 15838

American (AMR) AF: 0.00144 AC: 50 AN: 34720

Ashkenazi Jewish (ASJ) AF: 0.0145 AC: 291 AN: 20058

East Asian (EAS) AF: 0.00 AC: 0 AN: 32114

South Asian (SAS) AF: 0.000318 AC: 20 AN: 62806

European-Finnish (FIN) AF: 0.0000204 AC: 1 AN: 49000

Middle Eastern (MID) AF: 0.00931 AC: 38 AN: 4080

European-Non Finnish (NFE) AF: 0.000922 AC: 294 AN: 318872

Other (OTH) AF: 0.00328 AC: 101 AN: 30766

GnomAD4 genome AF: 0.00115 AC: 175 AN: 152316 Hom.: 3 Cov.: 33 AF XY: 0.00107 AC XY: 80 AN XY: 74470

African (AFR) AF: 0.000553 AC: 23 AN: 41568

American (AMR) AF: 0.00111 AC: 17 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0156 AC: 54 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5196

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.0204 AC: 6 AN: 294

European-Non Finnish (NFE) AF: 0.000941 AC: 64 AN: 68024

Other (OTH) AF: 0.00520 AC: 11 AN: 2114

Alfa AF: 0.00152 Hom.: 3

Bravo AF: 0.00129

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000519 AC: 2

ExAC AF: 0.00162 AC: 40

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	1	-	Autosomal recessive nonsyndromic hearing loss 77 (1)
-	-	1	LOXHD1-related disorder (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	6.7
DANN	Benign	0.87
Eigen	Benign	-0.45
Eigen_PC	Benign	-0.59
FATHMM_MKL	Benign	0.044	N
LIST_S2	Benign	0.53	T
M_CAP	Benign	0.051	D
MetaRNN	Benign	0.0057	T
MetaSVM	Benign	-1.0	T
PhyloP100		0.0080
PROVEAN	Benign	0.51	N
REVEL	Benign	0.011
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Vest4		0.22
MutPred		0.43		Gain of solvent accessibility (P = 0.0037)
MVP		0.11
ClinPred		0.017	T
GERP RS		1.3
Mutation Taster		=99/1	polymorphism

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs142931455; hg19: chr18-44057151;