NM_001384474.1:c.2T>A

Variant names:

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

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 1P and 16B. PVS1_Supporting 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

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]

ACMG classification

Verdict is Benign. Variant got -15 ACMG points.

• PVS1: Start lost variant, no pathogenic variants between lost start and next in-frame start position. 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 [Likely_benign]. Clinvar id 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LOXHD1	NM_001384474.1	c.2T>A	p.Met1?	start_lost	Exon 1 of 41	ENST00000642948.1	NP_001371403.1
LOXHD1	NM_144612.7	c.2T>A	p.Met1?	start_lost	Exon 1 of 40		NP_653213.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LOXHD1	ENST00000642948.1	c.2T>A	p.Met1?	start_lost	Exon 1 of 41		NM_001384474.1	ENSP00000496347.1
LOXHD1	ENST00000536736.5	c.2T>A	p.Met1?	start_lost	Exon 1 of 40	5		ENSP00000444586.1
LOXHD1	ENST00000441551.6	c.2T>A	p.Met1?	start_lost	Exon 1 of 39	5		ENSP00000387621.2

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

GnomAD3 exomes AF: 0.0323 AC: 4970 AN: 154084 Hom.: 136 AF XY: 0.0353 AC XY: 2887 AN XY: 81758

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 SAS exome AF: 0.0642

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

Gnomad4 AFR exome AF: 0.00579

Gnomad4 AMR exome AF: 0.0225

Gnomad4 ASJ exome AF: 0.0637

Gnomad4 EAS exome AF: 0.000252

Gnomad4 SAS exome AF: 0.0662

Gnomad4 FIN exome AF: 0.0228

Gnomad4 NFE exome AF: 0.0300

Gnomad4 OTH exome AF: 0.0323

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

Gnomad4 AFR AF: 0.00662

Gnomad4 AMR AF: 0.0252

Gnomad4 ASJ AF: 0.0675

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0595

Gnomad4 FIN AF: 0.0267

Gnomad4 NFE AF: 0.0330

Gnomad4 OTH AF: 0.0326

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

Significance: Benign/Likely benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Autosomal recessive nonsyndromic hearing loss 77 Benign:4

Sep 16, 2020

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jul 10, 2021

Genome-Nilou Lab

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 06, 2017

Counsyl

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

not specified Benign:3

Dec 20, 2012

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant has been identified in 4% (127/3182) of European American chromosom es from a broad population by the NHLBI Exome Sequencing Project (http://evs.gs. washington.edu/EVS/; dbSNP rs36024592) . There is also a second Met amino acid t hat may serve as the start of translation. -

Aug 25, 2017

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Feb 18, 2022

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: LOXHD1 c.2T>A (p.Met1Lys) alters the initiation codon and is predicted to result either in absence of the protein or truncation of the encoded protein due to translation initiation at a downstream codon. An alternative downstream in-frame start codon (Met2) is located in the encoded protein. One of two in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.032 in 154084 control chromosomes, predominantly at a frequency of 0.064 within the South Asian subpopulation in the gnomAD database, including 69 homozygotes. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 57 fold of the estimated maximal expected allele frequency for a pathogenic variant in LOXHD1 causing Nonsyndromic Hearing Loss And Deafness, Type 77 phenotype (0.0011), strongly suggesting that the variant is a benign polymorphism found primarily in populations of South Asian origin. To our knowledge, no experimental evidence demonstrating its impact on protein function have been reported. Seven ClinVar submitters (evaluation after 2014) cite the variant as benign (n=5) and likely benign (n=2). Based on the evidence outlined above, the variant was classified as benign. -

not provided Benign:3

Jan 27, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Aug 31, 2018

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

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;D;D
MetaRNN	Benign	0.0036	T;T;T
MetaSVM	Benign	-0.82	T
PROVEAN	Benign	-0.22	N;.;.
REVEL	Benign	0.22
Sift	Pathogenic	0.0	D;.;.
Sift4G	Pathogenic	0.0	D;.;D
Polyphen		0.60	P;.;.
Vest4		0.33
ClinPred		0.060	T
GERP RS		4.2
Varity_R		0.58
gMVP		0.94

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

Publications

LitVar

Other links and lift over

dbSNP: rs36024592; hg19: chr18-44236995; COSMIC: COSV71601157;