rs1555651404

Variant names:

• chr18-46477903-A-ACTTCCT
• rs1555651404
• NM_001384474.1:c.6385_6390dupAGGAAG

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PM4

The NM_001384474.1(LOXHD1):​c.6385_6390dupAGGAAG​(p.Lys2130_Tyr2131insArgLys) variant causes a conservative inframe insertion change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000043 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: LOXHD1 NM_001384474.1 conservative_inframe_insertion
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.198
• Publications: 0 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: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_001384474.1.

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.6385_6390dupAGGAAG	p.Lys2130_Tyr2131insArgLys	conservative_inframe_insertion	Exon 41 of 41	NP_001371403.1	A0A2R8Y7K4
	LOXHD1	NM_144612.7		c.6199_6204dupAGGAAG	p.Lys2068_Tyr2069insArgLys	conservative_inframe_insertion	Exon 40 of 40	NP_653213.6
	LOXHD1	NM_001145472.3		c.3052_3057dupAGGAAG	p.Lys1019_Tyr1020insArgLys	conservative_inframe_insertion	Exon 23 of 24	NP_001138944.1	Q8IVV2-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LOXHD1	ENST00000642948.1	MANE Select	c.6385_6390dupAGGAAG	p.Lys2130_Tyr2131insArgLys	conservative_inframe_insertion	Exon 41 of 41	ENSP00000496347.1	A0A2R8Y7K4
	LOXHD1	ENST00000300591.11	TSL:1	c.3052_3057dupAGGAAG	p.Lys1019_Tyr1020insArgLys	conservative_inframe_insertion	Exon 23 of 24	ENSP00000300591.6	Q8IVV2-3
	LOXHD1	ENST00000579038.6	TSL:1	c.2764_2769dupAGGAAG	p.Lys923_Tyr924insArgLys	conservative_inframe_insertion	Exon 21 of 22	ENSP00000463285.1	J3QKX9

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000429 AC: 6 AN: 1399088 Hom.: 0 Cov.: 31 AF XY: 0.00000580 AC XY: 4 AN XY: 689966

African (AFR) AF: 0.00 AC: 0 AN: 31596

American (AMR) AF: 0.00 AC: 0 AN: 35704

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25180

East Asian (EAS) AF: 0.00 AC: 0 AN: 35724

South Asian (SAS) AF: 0.00 AC: 0 AN: 79236

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49300

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5696

European-Non Finnish (NFE) AF: 0.00000556 AC: 6 AN: 1078642

Other (OTH) AF: 0.00 AC: 0 AN: 58010

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.20

Splicing

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

Other links and lift over

dbSNP: rs1555651404; hg19: chr18-44057866;