rs142960762

Positions:

• chr18-46560316-CTCT-C

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP3 BP6_Very_Strong BS1 BS2

The NM_001384474.1(LOXHD1):​c.2825_2827delAGA​(p.Lys942del) variant causes a disruptive inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0185 in 1,551,740 control chromosomes in the GnomAD database, including 370 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.014 (24 hom., cov: 31)
  • Exomes 𝑓: 0.019 (346 hom.)
• Consequence: LOXHD1 NM_001384474.1 disruptive_inframe_deletion
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 2.27

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 -17 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_001384474.1
• BP6: Variant 18-46560316-CTCT-C is Benign according to our data. Variant chr18-46560316-CTCT-C is described in ClinVar as [Likely_benign]. Clinvar id is 226714.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr18-46560316-CTCT-C is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0142 (2156/152250) while in subpopulation SAS AF= 0.0409 (197/4818). AF 95% confidence interval is 0.0362. There are 24 homozygotes in gnomad4. There are 1005 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 24 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LOXHD1	NM_001384474.1	c.2825_2827delAGA	p.Lys942del	disruptive_inframe_deletion	19/41	ENST00000642948.1	NP_001371403.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LOXHD1	ENST00000642948.1	c.2825_2827delAGA	p.Lys942del	disruptive_inframe_deletion	19/41		NM_001384474.1	ENSP00000496347.1
LOXHD1	ENST00000536736.5	c.2825_2827delAGA	p.Lys942del	disruptive_inframe_deletion	19/40	5		ENSP00000444586.1
LOXHD1	ENST00000441551.6	c.2598+2746_2598+2748delAGA		intron_variant		5		ENSP00000387621.2
LOXHD1	ENST00000335730.6	n.2138_2140delAGA		non_coding_transcript_exon_variant	12/27	2

Frequencies

GnomAD3 genomes AF: 0.0142 AC: 2154 AN: 152134 Hom.: 24 Cov.: 31

Gnomad AFR AF: 0.00367

Gnomad AMI AF: 0.0626

Gnomad AMR AF: 0.00727

Gnomad ASJ AF: 0.0280

Gnomad EAS AF: 0.00986

Gnomad SAS AF: 0.0406

Gnomad FIN AF: 0.00424

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.0206

Gnomad OTH AF: 0.0172

GnomAD3 exomes AF: 0.0182 AC: 2865 AN: 157278 Hom.: 52 AF XY: 0.0202 AC XY: 1670 AN XY: 82854

Gnomad AFR exome AF: 0.00384

Gnomad AMR exome AF: 0.00698

Gnomad ASJ exome AF: 0.0281

Gnomad EAS exome AF: 0.00731

Gnomad SAS exome AF: 0.0399

Gnomad FIN exome AF: 0.00492

Gnomad NFE exome AF: 0.0209

Gnomad OTH exome AF: 0.0175

GnomAD4 exome AF: 0.0190 AC: 26562 AN: 1399490 Hom.: 346 AF XY: 0.0200 AC XY: 13780 AN XY: 690308

Gnomad4 AFR exome AF: 0.00377

Gnomad4 AMR exome AF: 0.00781

Gnomad4 ASJ exome AF: 0.0293

Gnomad4 EAS exome AF: 0.0265

Gnomad4 SAS exome AF: 0.0403

Gnomad4 FIN exome AF: 0.00497

Gnomad4 NFE exome AF: 0.0182

Gnomad4 OTH exome AF: 0.0203

GnomAD4 genome AF: 0.0142 AC: 2156 AN: 152250 Hom.: 24 Cov.: 31 AF XY: 0.0135 AC XY: 1005 AN XY: 74418

Gnomad4 AFR AF: 0.00366

Gnomad4 AMR AF: 0.00726

Gnomad4 ASJ AF: 0.0280

Gnomad4 EAS AF: 0.00988

Gnomad4 SAS AF: 0.0409

Gnomad4 FIN AF: 0.00424

Gnomad4 NFE AF: 0.0206

Gnomad4 OTH AF: 0.0170

Alfa AF: 0.0192 Hom.: 2

Bravo AF: 0.0131

Asia WGS AF: 0.0170 AC: 58 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 24, 2015	p.Lys942del in exon 19 of LOXHD1: This variant is not expected to have clinical significance because it has been identified in 4.1% (327/7914) of South Asian ch romosomes, including 15 homozygotes, by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs142960762). -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 22, 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	Eurofins Ntd Llc (ga)	Aug 07, 2018	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Autosomal recessive nonsyndromic hearing loss 77 Benign:2

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	Counsyl	Mar 06, 2017	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Sep 12, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

Computational scores

Source: dbNSFP v4.3

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: rs142960762; hg19: chr18-44140279;