NM_001384474.1:c.6783G>A

Variant names:

• chr18-46477511-C-T
• rs115835484
• NM_001384474.1:c.6783G>A

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.6783G>A​(p.Gly2261Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0005 in 1,550,738 control chromosomes in the GnomAD database, including 4 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 0.0026 (2 hom., cov: 32)
  • Exomes 𝑓: 0.00027 (2 hom.)
• Consequence: LOXHD1 NM_001384474.1 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: -2.27
• 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: 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=-0.56).
• BP6: Variant 18-46477511-C-T is Benign according to our data. Variant chr18-46477511-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 163883.
• BP7: Synonymous conserved (PhyloP=-2.27 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00263 (401/152332) while in subpopulation AFR AF = 0.0094 (391/41580). AF 95% confidence interval is 0.00863. There are 2 homozygotes in GnomAd4. There are 195 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 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.6783G>A	p.Gly2261Gly	synonymous	Exon 41 of 41	NP_001371403.1	A0A2R8Y7K4
	LOXHD1	NM_144612.7		c.6597G>A	p.Gly2199Gly	synonymous	Exon 40 of 40	NP_653213.6
	LOXHD1	NM_001145473.3		c.1500G>A	p.Gly500Gly	synonymous	Exon 9 of 9	NP_001138945.1	Q8IVV2-5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LOXHD1	ENST00000642948.1	MANE Select	c.6783G>A	p.Gly2261Gly	synonymous	Exon 41 of 41	ENSP00000496347.1	A0A2R8Y7K4
	LOXHD1	ENST00000398686.8	TSL:1	c.1500G>A	p.Gly500Gly	synonymous	Exon 9 of 9	ENSP00000381676.4	Q8IVV2-5
	LOXHD1	ENST00000300591.11	TSL:1	c.3307+143G>A		intron	N/A	ENSP00000300591.6	Q8IVV2-3

Frequencies

GnomAD3 genomes AF: 0.00263 AC: 400 AN: 152214 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.00941

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000393

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00143

GnomAD2 exomes AF: 0.000614 AC: 94 AN: 153160 AF XY: 0.000516

Gnomad AFR exome AF: 0.0101

Gnomad AMR exome AF: 0.000446

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000508

Gnomad OTH exome AF: 0.000463

GnomAD4 exome AF: 0.000268 AC: 375 AN: 1398406 Hom.: 2 Cov.: 31 AF XY: 0.000213 AC XY: 147 AN XY: 689738

African (AFR) AF: 0.0100 AC: 317 AN: 31566

American (AMR) AF: 0.000392 AC: 14 AN: 35702

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 35730

South Asian (SAS) AF: 0.0000379 AC: 3 AN: 79198

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49128

Middle Eastern (MID) AF: 0.000396 AC: 2 AN: 5054

European-Non Finnish (NFE) AF: 0.00000649 AC: 7 AN: 1078922

Other (OTH) AF: 0.000552 AC: 32 AN: 57924

GnomAD4 genome AF: 0.00263 AC: 401 AN: 152332 Hom.: 2 Cov.: 32 AF XY: 0.00262 AC XY: 195 AN XY: 74490

African (AFR) AF: 0.00940 AC: 391 AN: 41580

American (AMR) AF: 0.000392 AC: 6 AN: 15302

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

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

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

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

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68036

Other (OTH) AF: 0.00142 AC: 3 AN: 2114

Alfa AF: 0.00130 Hom.: 1

Bravo AF: 0.00305

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	1	-	Autosomal recessive nonsyndromic hearing loss 77 (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.56
CADD	Benign	0.95
DANN	Benign	0.59
PhyloP100		-2.3
Mutation Taster		=96/4	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: rs115835484; hg19: chr18-44057474;