18-46569740-T-C

Variant names:

• chr18-46569740-T-C
• rs1824682
• NM_001384474.1:c.2048-102A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001384474.1(LOXHD1):​c.2048-102A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.231 in 892,746 control chromosomes in the GnomAD database, including 25,623 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.27 (6183 hom., cov: 32)
  • Exomes 𝑓: 0.22 (19440 hom.)
• Consequence: LOXHD1 NM_001384474.1 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -3.04
• Publications: 3 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.94).
• BP6: Variant 18-46569740-T-C is Benign according to our data. Variant chr18-46569740-T-C is described in ClinVar as Benign. ClinVar VariationId is 1184659.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.403 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LOXHD1	NM_001384474.1	MANE Select	c.2048-102A>G		intron	N/A	NP_001371403.1
	LOXHD1	NM_144612.7		c.2048-102A>G		intron	N/A	NP_653213.6

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LOXHD1	ENST00000642948.1	MANE Select	c.2048-102A>G		intron	N/A	ENSP00000496347.1
	LOXHD1	ENST00000536736.5	TSL:5	c.2048-102A>G		intron	N/A	ENSP00000444586.1
	LOXHD1	ENST00000441551.6	TSL:5	c.2048-102A>G		intron	N/A	ENSP00000387621.2

Frequencies

GnomAD3 genomes AF: 0.266 AC: 40458 AN: 151908 Hom.: 6150 Cov.: 32

Gnomad AFR AF: 0.407

Gnomad AMI AF: 0.302

Gnomad AMR AF: 0.205

Gnomad ASJ AF: 0.247

Gnomad EAS AF: 0.0742

Gnomad SAS AF: 0.241

Gnomad FIN AF: 0.161

Gnomad MID AF: 0.272

Gnomad NFE AF: 0.228

Gnomad OTH AF: 0.271

GnomAD4 exome AF: 0.224 AC: 166026 AN: 740720 Hom.: 19440 AF XY: 0.225 AC XY: 83935 AN XY: 372988

African (AFR) AF: 0.415 AC: 7518 AN: 18118

American (AMR) AF: 0.156 AC: 3332 AN: 21378

Ashkenazi Jewish (ASJ) AF: 0.252 AC: 3915 AN: 15542

East Asian (EAS) AF: 0.0642 AC: 2070 AN: 32232

South Asian (SAS) AF: 0.253 AC: 12009 AN: 47436

European-Finnish (FIN) AF: 0.154 AC: 6222 AN: 40498

Middle Eastern (MID) AF: 0.318 AC: 826 AN: 2594

European-Non Finnish (NFE) AF: 0.231 AC: 121759 AN: 527510

Other (OTH) AF: 0.237 AC: 8375 AN: 35412

GnomAD4 genome AF: 0.267 AC: 40550 AN: 152026 Hom.: 6183 Cov.: 32 AF XY: 0.260 AC XY: 19302 AN XY: 74324

African (AFR) AF: 0.408 AC: 16902 AN: 41438

American (AMR) AF: 0.205 AC: 3130 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.247 AC: 856 AN: 3468

East Asian (EAS) AF: 0.0740 AC: 383 AN: 5174

South Asian (SAS) AF: 0.242 AC: 1165 AN: 4816

European-Finnish (FIN) AF: 0.161 AC: 1701 AN: 10586

Middle Eastern (MID) AF: 0.282 AC: 83 AN: 294

European-Non Finnish (NFE) AF: 0.228 AC: 15478 AN: 67948

Other (OTH) AF: 0.274 AC: 577 AN: 2108

Alfa AF: 0.235 Hom.: 3847

Bravo AF: 0.276

Asia WGS AF: 0.190 AC: 661 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Autosomal recessive nonsyndromic hearing loss 77 Benign:1

Jul 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Benign:1

May 12, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	0.013
DANN	Benign	0.21
PhyloP100		-3.0
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: rs1824682; hg19: chr18-44149703;