rs36024592

Variant names:

• chr18-46657032-A-T
• rs36024592
• NM_001384474.1:c.2T>A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 2P and 16B. PVS1_Moderate BP6_Very_Strong BA1

The NM_001384474.1(LOXHD1):​c.2T>A​(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0304 in 1,551,572 control chromosomes in the GnomAD database, including 917 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.025 (70 hom., cov: 32)
  • Exomes 𝑓: 0.031 (847 hom.)
• Consequence: LOXHD1 NM_001384474.1 start_lost
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 2.84
• Publications: 16 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, PanelApp Australia, 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.

• PVS1: Start lost variant, next in-frame start position is after 1 pathogenic variants. Next in-frame start position is after 2 codons. Genomic position: 46657030. Lost 0.001 part of the original CDS.
• BP6: Variant 18-46657032-A-T is Benign according to our data. Variant chr18-46657032-A-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 47932.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0539 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.2T>A	p.Met1?	start_lost	Exon 1 of 41	NP_001371403.1	A0A2R8Y7K4
	LOXHD1	NM_144612.7		c.2T>A	p.Met1?	start_lost	Exon 1 of 40	NP_653213.6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LOXHD1	ENST00000642948.1	MANE Select	c.2T>A	p.Met1?	start_lost	Exon 1 of 41	ENSP00000496347.1	A0A2R8Y7K4
	LOXHD1	ENST00000536736.5	TSL:5	c.2T>A	p.Met1?	start_lost	Exon 1 of 40	ENSP00000444586.1	F5GZB4
	LOXHD1	ENST00000441551.6	TSL:5	c.2T>A	p.Met1?	start_lost	Exon 1 of 39	ENSP00000387621.2	Q8IVV2-1

Frequencies

GnomAD3 genomes AF: 0.0251 AC: 3825 AN: 152136 Hom.: 71 Cov.: 32

Gnomad AFR AF: 0.00666

Gnomad AMI AF: 0.0373

Gnomad AMR AF: 0.0252

Gnomad ASJ AF: 0.0675

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0599

Gnomad FIN AF: 0.0267

Gnomad MID AF: 0.0348

Gnomad NFE AF: 0.0330

Gnomad OTH AF: 0.0325

GnomAD2 exomes AF: 0.0323 AC: 4970 AN: 154084 AF XY: 0.0353

Gnomad AFR exome AF: 0.00517

Gnomad AMR exome AF: 0.0218

Gnomad ASJ exome AF: 0.0661

Gnomad EAS exome AF: 0.000183

Gnomad FIN exome AF: 0.0218

Gnomad NFE exome AF: 0.0315

Gnomad OTH exome AF: 0.0343

GnomAD4 exome AF: 0.0310 AC: 43398 AN: 1399318 Hom.: 847 Cov.: 31 AF XY: 0.0323 AC XY: 22273 AN XY: 690184

African (AFR) AF: 0.00579 AC: 183 AN: 31598

American (AMR) AF: 0.0225 AC: 803 AN: 35692

Ashkenazi Jewish (ASJ) AF: 0.0637 AC: 1604 AN: 25178

East Asian (EAS) AF: 0.000252 AC: 9 AN: 35738

South Asian (SAS) AF: 0.0662 AC: 5244 AN: 79236

European-Finnish (FIN) AF: 0.0228 AC: 1122 AN: 49276

Middle Eastern (MID) AF: 0.0365 AC: 208 AN: 5698

European-Non Finnish (NFE) AF: 0.0300 AC: 32353 AN: 1078902

Other (OTH) AF: 0.0323 AC: 1872 AN: 58000

GnomAD4 genome AF: 0.0251 AC: 3822 AN: 152254 Hom.: 70 Cov.: 32 AF XY: 0.0252 AC XY: 1875 AN XY: 74434

African (AFR) AF: 0.00662 AC: 275 AN: 41548

American (AMR) AF: 0.0252 AC: 385 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0675 AC: 234 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5158

South Asian (SAS) AF: 0.0595 AC: 287 AN: 4820

European-Finnish (FIN) AF: 0.0267 AC: 284 AN: 10628

Middle Eastern (MID) AF: 0.0340 AC: 10 AN: 294

European-Non Finnish (NFE) AF: 0.0330 AC: 2244 AN: 68012

Other (OTH) AF: 0.0326 AC: 69 AN: 2114

Alfa AF: 0.0322 Hom.: 77

Bravo AF: 0.0232

TwinsUK AF: 0.0313 AC: 116

ALSPAC AF: 0.0324 AC: 125

ESP6500AA AF: 0.00650 AC: 9

ESP6500EA AF: 0.0399 AC: 127

ExAC AF: 0.0374 AC: 952

Asia WGS AF: 0.0210 AC: 73 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.16
CADD	Benign	20
DANN	Benign	0.89
DEOGEN2	Benign	0.014	T
Eigen	Benign	-0.11
Eigen_PC	Benign	-0.090
FATHMM_MKL	Benign	0.68	D
LIST_S2	Uncertain	0.90	D
MetaRNN	Benign	0.0036	T
MetaSVM	Benign	-0.82	T
PhyloP100		2.8
PROVEAN	Benign	-0.22	N
REVEL	Benign	0.22
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.60	P
Vest4		0.33
ClinPred		0.060	T
GERP RS		4.2
PromoterAI		-0.0074	Neutral
Varity_R		0.58
gMVP		0.94
Mutation Taster		=99/1	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: rs36024592; hg19: chr18-44236995; COSMIC: COSV71601157;