18-46657032-A-T

Position:

chr18-46657032-A-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 8P and 16B. PVS1BP6_Very_StrongBA1

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

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: 2.84

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

PVS1

Start lost variant, no new inframe start found.

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/exons	MANE	Protein	UniProt
LOXHD1	NM_001384474.1 linkuse as main transcript	c.2T>A	p.Met1?	start_lost	1/41	ENST00000642948.1	NP_001371403.1
LOXHD1	NM_144612.7 linkuse as main transcript	c.2T>A	p.Met1?	start_lost	1/40		NP_653213.6	Q8IVV2F5GZB4B7Z7T7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
LOXHD1	ENST00000642948.1 linkuse as main transcript	c.2T>A	p.Met1?	start_lost	1/41		NM_001384474.1	ENSP00000496347.1	A0A2R8Y7K4
LOXHD1	ENST00000536736.5 linkuse as main transcript	c.2T>A	p.Met1?	start_lost	1/40	5		ENSP00000444586.1	F5GZB4
LOXHD1	ENST00000441551.6 linkuse as main transcript	c.2T>A	p.Met1?	start_lost	1/39	5		ENSP00000387621.2	Q8IVV2-1

Frequencies

GnomAD3 genomes

AF:

0.0251

AC:

3825

AN:

152136

Hom.:

Cov.:

show subpopulations

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

show subpopulations

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.:

AF XY:

0.0323

AC XY:

22273

AN XY:

690184

show subpopulations

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.:

Cov.:

AF XY:

0.0252

AC XY:

1875

AN XY:

74434

show subpopulations

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.:

Bravo

AF:

0.0232

TwinsUK

AF:

0.0313

AC:

116

ALSPAC

AF:

0.0324

AC:

125

ESP6500AA

AF:

0.00650

AC:

ESP6500EA

AF:

0.0399

AC:

127

ExAC

AF:

0.0374

AC:

952

Asia WGS

AF:

0.0210

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Autosomal recessive nonsyndromic hearing loss 77

Benign:4

Likely benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 10, 2021	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	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. -
Benign, criteria provided, single submitter	clinical testing	Counsyl	Mar 06, 2017	- -

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Dec 20, 2012	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. -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 25, 2017	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. -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 18, 2022	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

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Aug 31, 2018	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.30

BayesDel_noAF

Benign

-0.16

CADD

Benign

DANN

Benign

0.89

DEOGEN2

Benign

0.014

.;.;T

Eigen

Benign

-0.11

Eigen_PC

Benign

-0.090

FATHMM_MKL

Benign

0.68

LIST_S2

Uncertain

0.90

D;D;D

MetaRNN

Benign

0.0036

T;T;T

MetaSVM

Benign

-0.82

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

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over