rs117403100

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001384474.1(LOXHD1):c.4531-19C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0351 in 1,551,238 control chromosomes in the GnomAD database, including 1,134 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.026 ( 79 hom., cov: 32)

Exomes 𝑓: 0.036 ( 1055 hom. )

Consequence

LOXHD1
NM_001384474.1 intron

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 0.474

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.74).

BP6

Variant 18-46524936-G-A is Benign according to our data. Variant chr18-46524936-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 262521.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0262 (3992/152242) while in subpopulation NFE AF= 0.0388 (2637/68000). AF 95% confidence interval is 0.0375. There are 79 homozygotes in gnomad4. There are 1915 alleles in male gnomad4 subpopulation. This position pass quality control queck.

BS2

High Homozygotes in GnomAd at 80 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LOXHD1	NM_001384474.1 linkuse as main transcript	c.4531-19C>T		intron_variant		ENST00000642948.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LOXHD1	ENST00000642948.1 linkuse as main transcript	c.4531-19C>T		intron_variant			NM_001384474.1	P1

Frequencies

GnomAD3 genomes

AF:

0.0263

AC:

3996

AN:

152126

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00707

Gnomad AMI

AF:

0.110

Gnomad AMR

AF:

0.0203

Gnomad ASJ

AF:

0.0447

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.0332

Gnomad FIN

AF:

0.0262

Gnomad MID

AF:

0.0190

Gnomad NFE

AF:

0.0388

Gnomad OTH

AF:

0.0268

GnomAD3 exomes

AF:

0.0288

AC:

4473

AN:

155554

Hom.:

109

AF XY:

0.0306

AC XY:

2512

AN XY:

82000

show subpopulations

Gnomad AFR exome

AF:

0.00668

Gnomad AMR exome

AF:

0.0152

Gnomad ASJ exome

AF:

0.0432

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0365

Gnomad FIN exome

AF:

0.0256

Gnomad NFE exome

AF:

0.0383

Gnomad OTH exome

AF:

0.0359

GnomAD4 exome

AF:

0.0360

AC:

50380

AN:

1398996

Hom.:

1055

Cov.:

AF XY:

0.0362

AC XY:

24985

AN XY:

690012

show subpopulations

Gnomad4 AFR exome

AF:

0.00567

Gnomad4 AMR exome

AF:

0.0161

Gnomad4 ASJ exome

AF:

0.0426

Gnomad4 EAS exome

AF:

0.0000280

Gnomad4 SAS exome

AF:

0.0363

Gnomad4 FIN exome

AF:

0.0280

Gnomad4 NFE exome

AF:

0.0391

Gnomad4 OTH exome

AF:

0.0340

GnomAD4 genome

AF:

0.0262

AC:

3992

AN:

152242

Hom.:

Cov.:

AF XY:

0.0257

AC XY:

1915

AN XY:

74448

show subpopulations

Gnomad4 AFR

AF:

0.00705

Gnomad4 AMR

AF:

0.0203

Gnomad4 ASJ

AF:

0.0447

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.0326

Gnomad4 FIN

AF:

0.0262

Gnomad4 NFE

AF:

0.0388

Gnomad4 OTH

AF:

0.0265

Alfa

AF:

0.0334

Hom.:

Bravo

AF:

0.0249

Asia WGS

AF:

0.0130

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 16, 2018	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	Invitae	Feb 01, 2024	- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

- -

Autosomal recessive nonsyndromic hearing loss 77

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 10, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.74

Cadd

Benign

6.3

Dann

Benign

0.75

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