rs114082868

Variant names:

• chr18-46601385-C-G
• rs114082868
• NM_001384474.1:c.966G>C

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6 BP7 BA1

The NM_001384474.1(LOXHD1):​c.966G>C​(p.Gly322Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00387 in 1,551,654 control chromosomes in the GnomAD database, including 170 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.019 (94 hom., cov: 32)
  • Exomes 𝑓: 0.0022 (76 hom.)
• Consequence: LOXHD1 NM_001384474.1 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:7
• Conservation: PhyloP100: -0.186
• 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: G2P, PanelApp Australia, Labcorp Genetics (formerly Invitae), Ambry Genetics
• 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 -10 ACMG points.

• BP6: Variant 18-46601385-C-G is Benign according to our data. Variant chr18-46601385-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 178615.
• BP7: Synonymous conserved (PhyloP=-0.186 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0644 is higher than 0.05.

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.966G>C	p.Gly322Gly	synonymous	Exon 8 of 41	NP_001371403.1
	LOXHD1	NM_144612.7		c.966G>C	p.Gly322Gly	synonymous	Exon 8 of 40	NP_653213.6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LOXHD1	ENST00000642948.1	MANE Select	c.966G>C	p.Gly322Gly	synonymous	Exon 8 of 41	ENSP00000496347.1
	LOXHD1	ENST00000536736.5	TSL:5	c.966G>C	p.Gly322Gly	synonymous	Exon 8 of 40	ENSP00000444586.1
	LOXHD1	ENST00000441551.6	TSL:5	c.966G>C	p.Gly322Gly	synonymous	Exon 8 of 39	ENSP00000387621.2

Frequencies

GnomAD3 genomes AF: 0.0191 AC: 2898 AN: 152120 Hom.: 93 Cov.: 32

Gnomad AFR AF: 0.0665

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00583

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.000382

Gnomad OTH AF: 0.0105

GnomAD2 exomes AF: 0.00495 AC: 785 AN: 158498 AF XY: 0.00347

Gnomad AFR exome AF: 0.0757

Gnomad AMR exome AF: 0.00335

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000459

Gnomad OTH exome AF: 0.00358

GnomAD4 exome AF: 0.00221 AC: 3094 AN: 1399416 Hom.: 76 Cov.: 32 AF XY: 0.00194 AC XY: 1339 AN XY: 690212

African (AFR) AF: 0.0686 AC: 2169 AN: 31598

American (AMR) AF: 0.00378 AC: 135 AN: 35704

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 35738

South Asian (SAS) AF: 0.000215 AC: 17 AN: 79236

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49280

Middle Eastern (MID) AF: 0.00351 AC: 20 AN: 5698

European-Non Finnish (NFE) AF: 0.000450 AC: 486 AN: 1078976

Other (OTH) AF: 0.00460 AC: 267 AN: 58004

GnomAD4 genome AF: 0.0191 AC: 2904 AN: 152238 Hom.: 94 Cov.: 32 AF XY: 0.0185 AC XY: 1374 AN XY: 74438

African (AFR) AF: 0.0665 AC: 2761 AN: 41520

American (AMR) AF: 0.00582 AC: 89 AN: 15294

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.000415 AC: 2 AN: 4818

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

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.000382 AC: 26 AN: 68012

Other (OTH) AF: 0.0104 AC: 22 AN: 2112

Alfa AF: 0.00750 Hom.: 6

Bravo AF: 0.0226

Asia WGS AF: 0.00231 AC: 8 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	2	Autosomal recessive nonsyndromic hearing loss 77 (3)
-	-	3	not specified (3)
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.36
CADD	Benign	7.9
DANN	Benign	0.70
PhyloP100		-0.19
Mutation Taster		=100/0	polymorphism (auto)

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: rs114082868; hg19: chr18-44181348;