rs779218726

Variant names:

• chr18-46485117-G-A
• rs779218726
• NM_001384474.1:c.6084C>T

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_Strong BP6_Moderate BP7

The NM_001384474.1(LOXHD1):​c.6084C>T​(p.Gly2028Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000071 in 1,549,088 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.000067 (0 hom., cov: 30)
  • Exomes 𝑓: 0.000071 (0 hom.)
• Consequence: LOXHD1 NM_001384474.1 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.626
• 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: 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 -7 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.67).
• BP6: Variant 18-46485117-G-A is Benign according to our data. Variant chr18-46485117-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 517332.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-0.626 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LOXHD1	NM_001384474.1	c.6084C>T	p.Gly2028Gly	synonymous_variant	Exon 39 of 41	ENST00000642948.1	NP_001371403.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LOXHD1	ENST00000642948.1	c.6084C>T	p.Gly2028Gly	synonymous_variant	Exon 39 of 41		NM_001384474.1	ENSP00000496347.1

Frequencies

GnomAD3 genomes AF: 0.0000668 AC: 10 AN: 149608 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.0000247

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000135

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000218

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000887

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000822 AC: 13 AN: 158176 AF XY: 0.0000838

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000917

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000162

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000715 AC: 100 AN: 1399364 Hom.: 0 Cov.: 35 AF XY: 0.0000652 AC XY: 45 AN XY: 690202

African (AFR) AF: 0.00 AC: 0 AN: 31592

American (AMR) AF: 0.0000280 AC: 1 AN: 35694

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25164

East Asian (EAS) AF: 0.0000280 AC: 1 AN: 35740

South Asian (SAS) AF: 0.000164 AC: 13 AN: 79198

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49474

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5694

European-Non Finnish (NFE) AF: 0.0000686 AC: 74 AN: 1078698

Other (OTH) AF: 0.000189 AC: 11 AN: 58110

GnomAD4 genome AF: 0.0000668 AC: 10 AN: 149724 Hom.: 0 Cov.: 30 AF XY: 0.0000686 AC XY: 5 AN XY: 72896

African (AFR) AF: 0.0000246 AC: 1 AN: 40578

American (AMR) AF: 0.000135 AC: 2 AN: 14802

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3454

East Asian (EAS) AF: 0.00 AC: 0 AN: 5088

South Asian (SAS) AF: 0.000219 AC: 1 AN: 4574

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10312

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.0000887 AC: 6 AN: 67652

Other (OTH) AF: 0.00 AC: 0 AN: 2064

Alfa AF: 0.0000987 Hom.: 0

Bravo AF: 0.0000604

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Apr 20, 2017

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

p.Gly1966Gly in exon 38 of LOXHD1: This variant is not expected to have clinical significance because it does not alter an amino acid residue and is not located within the splice consensus sequence. This variant has been identified in 1/927 0 European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.br oadinstitute.org; dbSNP rs779218726). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.67
CADD	Benign	7.4
DANN	Benign	0.72
PhyloP100		-0.63

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.16		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: rs779218726; hg19: chr18-44065080; COSMIC: COSV56072575;