rs759237437

Variant names:

• chr18-46560252-C-CGAGGACTCCTCTGATGAG
• rs759237437
• NM_001384474.1:c.2874_2891dupCTCATCAGAGGAGTCCTC

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP3 BP6 BS2

The NM_001384474.1(LOXHD1):​c.2874_2891dupCTCATCAGAGGAGTCCTC​(p.Ser964_Ser965insSerSerGluGluSerSer) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00166 in 1,551,366 control chromosomes in the GnomAD database, including 3 homozygotes. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. S964S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0011 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0017 (3 hom.)
• Consequence: LOXHD1 NM_001384474.1 disruptive_inframe_insertion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:3
• Conservation: PhyloP100: 1.41
• Publications: 2 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, 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: Likely_benign. The variant received -6 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_001384474.1
• BP6: Variant 18-46560252-C-CGAGGACTCCTCTGATGAG is Benign according to our data. Variant chr18-46560252-C-CGAGGACTCCTCTGATGAG is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 228821.
• BS2: High Homozygotes in GnomAdExome4 at 3 AR,AD gene

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.2874_2891dupCTCATCAGAGGAGTCCTC	p.Ser964_Ser965insSerSerGluGluSerSer	disruptive_inframe_insertion	Exon 19 of 41	NP_001371403.1	A0A2R8Y7K4
	LOXHD1	NM_144612.7		c.2874_2891dupCTCATCAGAGGAGTCCTC	p.Ser964_Ser965insSerSerGluGluSerSer	disruptive_inframe_insertion	Exon 19 of 40	NP_653213.6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LOXHD1	ENST00000642948.1	MANE Select	c.2874_2891dupCTCATCAGAGGAGTCCTC	p.Ser964_Ser965insSerSerGluGluSerSer	disruptive_inframe_insertion	Exon 19 of 41	ENSP00000496347.1	A0A2R8Y7K4
	LOXHD1	ENST00000536736.5	TSL:5	c.2874_2891dupCTCATCAGAGGAGTCCTC	p.Ser964_Ser965insSerSerGluGluSerSer	disruptive_inframe_insertion	Exon 19 of 40	ENSP00000444586.1	F5GZB4
	LOXHD1	ENST00000441551.6	TSL:5	c.2599-2781_2599-2764dupCTCATCAGAGGAGTCCTC		intron	N/A	ENSP00000387621.2	Q8IVV2-1

Frequencies

GnomAD3 genomes AF: 0.00108 AC: 164 AN: 152154 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000265

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00275

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000659

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00141

Gnomad OTH AF: 0.00335

GnomAD2 exomes AF: 0.00113 AC: 179 AN: 158546 AF XY: 0.00107

Gnomad AFR exome AF: 0.000113

Gnomad AMR exome AF: 0.00141

Gnomad ASJ exome AF: 0.000353

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000721

Gnomad NFE exome AF: 0.00199

Gnomad OTH exome AF: 0.00111

GnomAD4 exome AF: 0.00173 AC: 2414 AN: 1399094 Hom.: 3 Cov.: 37 AF XY: 0.00169 AC XY: 1166 AN XY: 690114

African (AFR) AF: 0.000222 AC: 7 AN: 31576

American (AMR) AF: 0.00162 AC: 58 AN: 35704

Ashkenazi Jewish (ASJ) AF: 0.000238 AC: 6 AN: 25180

East Asian (EAS) AF: 0.00 AC: 0 AN: 35742

South Asian (SAS) AF: 0.0000126 AC: 1 AN: 79226

European-Finnish (FIN) AF: 0.00111 AC: 55 AN: 49404

Middle Eastern (MID) AF: 0.000175 AC: 1 AN: 5700

European-Non Finnish (NFE) AF: 0.00208 AC: 2239 AN: 1078506

Other (OTH) AF: 0.000810 AC: 47 AN: 58056

GnomAD4 genome AF: 0.00108 AC: 164 AN: 152272 Hom.: 0 Cov.: 32 AF XY: 0.000954 AC XY: 71 AN XY: 74452

African (AFR) AF: 0.000265 AC: 11 AN: 41566

American (AMR) AF: 0.00274 AC: 42 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5162

South Asian (SAS) AF: 0.00 AC: 0 AN: 4816

European-Finnish (FIN) AF: 0.000659 AC: 7 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00141 AC: 96 AN: 68016

Other (OTH) AF: 0.00331 AC: 7 AN: 2114

Alfa AF: 0.000735 Hom.: 0

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	Autosomal recessive nonsyndromic hearing loss 77 (2)
-	1	1	not provided (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.4
Mutation Taster		=66/34	polymorphism

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs759237437; hg19: chr18-44140215; COSMIC: COSV56069228; COSMIC: COSV56069228;