18-46524734-G-T

Variant names:

• chr18-46524734-G-T
• rs75949023
• NM_001384474.1:c.4714C>A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001384474.1(LOXHD1):​c.4714C>A​(p.Arg1572Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00412 in 1,551,660 control chromosomes in the GnomAD database, including 156 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0073 (28 hom., cov: 33)
  • Exomes 𝑓: 0.0038 (128 hom.)
• Consequence: LOXHD1 NM_001384474.1 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 2.14
• Publications: 22 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.47).
• BP6: Variant 18-46524734-G-T is Benign according to our data. Variant chr18-46524734-G-T is described in ClinVar as Benign. ClinVar VariationId is 47940.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=2.14 with no splicing effect.
• BA1: GnomAdExome4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0549 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.4714C>A	p.Arg1572Arg	synonymous	Exon 30 of 41	NP_001371403.1	A0A2R8Y7K4
	LOXHD1	NM_144612.7		c.4714C>A	p.Arg1572Arg	synonymous	Exon 30 of 40	NP_653213.6
	LOXHD1	NM_001145472.3		c.1381C>A	p.Arg461Arg	synonymous	Exon 12 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.4714C>A	p.Arg1572Arg	synonymous	Exon 30 of 41	ENSP00000496347.1	A0A2R8Y7K4
	LOXHD1	ENST00000300591.11	TSL:1	c.1381C>A	p.Arg461Arg	synonymous	Exon 12 of 24	ENSP00000300591.6	Q8IVV2-3
	LOXHD1	ENST00000579038.6	TSL:1	c.1093C>A	p.Arg365Arg	synonymous	Exon 10 of 22	ENSP00000463285.1	J3QKX9

Frequencies

GnomAD3 genomes AF: 0.00730 AC: 1111 AN: 152150 Hom.: 28 Cov.: 33

Gnomad AFR AF: 0.00164

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0360

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.0404

Gnomad SAS AF: 0.00310

Gnomad FIN AF: 0.0177

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00107

Gnomad OTH AF: 0.00335

GnomAD2 exomes AF: 0.0145 AC: 2287 AN: 157920 AF XY: 0.0118

Gnomad AFR exome AF: 0.00196

Gnomad AMR exome AF: 0.0603

Gnomad ASJ exome AF: 0.000118

Gnomad EAS exome AF: 0.0373

Gnomad FIN exome AF: 0.0139

Gnomad NFE exome AF: 0.000627

Gnomad OTH exome AF: 0.00742

GnomAD4 exome AF: 0.00378 AC: 5289 AN: 1399392 Hom.: 128 Cov.: 32 AF XY: 0.00354 AC XY: 2441 AN XY: 690202

African (AFR) AF: 0.00127 AC: 40 AN: 31598

American (AMR) AF: 0.0569 AC: 2032 AN: 35704

Ashkenazi Jewish (ASJ) AF: 0.0000794 AC: 2 AN: 25182

East Asian (EAS) AF: 0.0456 AC: 1630 AN: 35738

South Asian (SAS) AF: 0.00247 AC: 196 AN: 79236

European-Finnish (FIN) AF: 0.0152 AC: 747 AN: 49258

Middle Eastern (MID) AF: 0.000878 AC: 5 AN: 5698

European-Non Finnish (NFE) AF: 0.000303 AC: 327 AN: 1078976

Other (OTH) AF: 0.00534 AC: 310 AN: 58002

GnomAD4 genome AF: 0.00730 AC: 1111 AN: 152268 Hom.: 28 Cov.: 33 AF XY: 0.00838 AC XY: 624 AN XY: 74460

African (AFR) AF: 0.00164 AC: 68 AN: 41552

American (AMR) AF: 0.0362 AC: 553 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3470

East Asian (EAS) AF: 0.0397 AC: 205 AN: 5166

South Asian (SAS) AF: 0.00331 AC: 16 AN: 4828

European-Finnish (FIN) AF: 0.0177 AC: 188 AN: 10620

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

European-Non Finnish (NFE) AF: 0.00107 AC: 73 AN: 68020

Other (OTH) AF: 0.00331 AC: 7 AN: 2112

Alfa AF: 0.000632 Hom.: 2

Bravo AF: 0.00832

Asia WGS AF: 0.0230 AC: 79 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	3	Autosomal recessive nonsyndromic hearing loss 77 (3)
-	-	3	not specified (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.47
CADD	Benign	2.7
DANN	Benign	0.53
PhyloP100		2.1
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: rs75949023; hg19: chr18-44104697; COSMIC: COSV105893009;