rs117297079

Variant names:

• chr18-46538252-G-A
• rs117297079
• NM_001384474.1:c.3999C>T

Your query was ambiguous. Multiple possible variants found:

• chr18-46538252-G-A
• chr18-46538252-G-T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BS1 BS2

The NM_001384474.1(LOXHD1):​c.3999C>T​(p.Cys1333Cys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00774 in 1,551,238 control chromosomes in the GnomAD database, including 58 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0062 (8 hom., cov: 32)
  • Exomes 𝑓: 0.0079 (50 hom.)
• Consequence: LOXHD1 NM_001384474.1 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:5
• Conservation: PhyloP100: -1.89
• Publications: 2 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.71).
• BP6: Variant 18-46538252-G-A is Benign according to our data. Variant chr18-46538252-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 47936.
• BP7: Synonymous conserved (PhyloP=-1.89 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00624 (950/152280) while in subpopulation NFE AF = 0.00878 (597/68018). AF 95% confidence interval is 0.00819. There are 8 homozygotes in GnomAd4. There are 501 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 8 AD,AR gene

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LOXHD1	NM_001384474.1	MANE Select	c.3999C>T	p.Cys1333Cys	synonymous	Exon 26 of 41	NP_001371403.1	A0A2R8Y7K4
	LOXHD1	NM_144612.7		c.3999C>T	p.Cys1333Cys	synonymous	Exon 26 of 40	NP_653213.6
	LOXHD1	NM_001145472.3		c.666C>T	p.Cys222Cys	synonymous	Exon 8 of 24	NP_001138944.1	Q8IVV2-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LOXHD1	ENST00000642948.1	MANE Select	c.3999C>T	p.Cys1333Cys	synonymous	Exon 26 of 41	ENSP00000496347.1	A0A2R8Y7K4
	LOXHD1	ENST00000300591.11	TSL:1	c.666C>T	p.Cys222Cys	synonymous	Exon 8 of 24	ENSP00000300591.6	Q8IVV2-3
	LOXHD1	ENST00000579038.6	TSL:1	c.378C>T	p.Cys126Cys	synonymous	Exon 6 of 22	ENSP00000463285.1	J3QKX9

Frequencies

GnomAD3 genomes AF: 0.00624 AC: 950 AN: 152162 Hom.: 8 Cov.: 32

Gnomad AFR AF: 0.00140

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00334

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0221

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00878

Gnomad OTH AF: 0.00430

GnomAD2 exomes AF: 0.00604 AC: 948 AN: 156950 AF XY: 0.00588

Gnomad AFR exome AF: 0.000575

Gnomad AMR exome AF: 0.00214

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0200

Gnomad NFE exome AF: 0.00887

Gnomad OTH exome AF: 0.00564

GnomAD4 exome AF: 0.00791 AC: 11059 AN: 1398958 Hom.: 50 Cov.: 31 AF XY: 0.00771 AC XY: 5316 AN XY: 689942

African (AFR) AF: 0.000791 AC: 25 AN: 31590

American (AMR) AF: 0.00246 AC: 88 AN: 35702

Ashkenazi Jewish (ASJ) AF: 0.000159 AC: 4 AN: 25182

East Asian (EAS) AF: 0.00 AC: 0 AN: 35722

South Asian (SAS) AF: 0.000417 AC: 33 AN: 79224

European-Finnish (FIN) AF: 0.0222 AC: 1094 AN: 49268

Middle Eastern (MID) AF: 0.00140 AC: 8 AN: 5696

European-Non Finnish (NFE) AF: 0.00874 AC: 9429 AN: 1078584

Other (OTH) AF: 0.00652 AC: 378 AN: 57990

GnomAD4 genome AF: 0.00624 AC: 950 AN: 152280 Hom.: 8 Cov.: 32 AF XY: 0.00673 AC XY: 501 AN XY: 74452

African (AFR) AF: 0.00140 AC: 58 AN: 41550

American (AMR) AF: 0.00333 AC: 51 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.0221 AC: 235 AN: 10610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00878 AC: 597 AN: 68018

Other (OTH) AF: 0.00425 AC: 9 AN: 2116

Alfa AF: 0.00697 Hom.: 5

Bravo AF: 0.00480

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
-	1	1	Autosomal recessive nonsyndromic hearing loss 77 (2)
-	-	2	not provided (2)
-	-	2	not specified (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.71
CADD	Benign	1.4
DANN	Benign	0.48
PhyloP100		-1.9
Mutation Taster		=100/0	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: rs117297079; hg19: chr18-44118215; COSMIC: COSV56061687;