rs397517864

Variant names:

• chr18-46485166-G-A
• rs397517864
• NM_001384474.1:c.6050-15C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BP6_Very_Strong

The NM_001384474.1(LOXHD1):​c.6050-15C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000106 in 1,547,414 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.000053 (0 hom., cov: 30)
  • Exomes 𝑓: 0.00011 (0 hom.)
• Consequence: LOXHD1 NM_001384474.1 intron
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts U:1 B:2
• Conservation: PhyloP100: 2.64
• 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: G2P, PanelApp Australia, Labcorp Genetics (formerly Invitae), Ambry Genetics
• 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.74).
• BP6: Variant 18-46485166-G-A is Benign according to our data. Variant chr18-46485166-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 47948.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LOXHD1	NM_001384474.1	MANE Select	c.6050-15C>T		intron	N/A	NP_001371403.1
	LOXHD1	NM_144612.7		c.5864-15C>T		intron	N/A	NP_653213.6
	LOXHD1	NM_001145472.3		c.2717-15C>T		intron	N/A	NP_001138944.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LOXHD1	ENST00000642948.1	MANE Select	c.6050-15C>T		intron	N/A	ENSP00000496347.1
	LOXHD1	ENST00000300591.11	TSL:1	c.2717-15C>T		intron	N/A	ENSP00000300591.6
	LOXHD1	ENST00000579038.6	TSL:1	c.2429-15C>T		intron	N/A	ENSP00000463285.1

Frequencies

GnomAD3 genomes AF: 0.0000532 AC: 8 AN: 150466 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000668

Gnomad ASJ AF: 0.000290

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000216

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000738

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000190 AC: 30 AN: 157968 AF XY: 0.000240

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00200

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000488

Gnomad OTH exome AF: 0.000223

GnomAD4 exome AF: 0.000112 AC: 156 AN: 1396830 Hom.: 0 Cov.: 35 AF XY: 0.000123 AC XY: 85 AN XY: 688404

African (AFR) AF: 0.00 AC: 0 AN: 31560

American (AMR) AF: 0.0000280 AC: 1 AN: 35652

Ashkenazi Jewish (ASJ) AF: 0.00231 AC: 58 AN: 25156

East Asian (EAS) AF: 0.00 AC: 0 AN: 35668

South Asian (SAS) AF: 0.000518 AC: 41 AN: 79082

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49384

Middle Eastern (MID) AF: 0.000527 AC: 3 AN: 5696

European-Non Finnish (NFE) AF: 0.0000372 AC: 40 AN: 1076636

Other (OTH) AF: 0.000224 AC: 13 AN: 57996

GnomAD4 genome AF: 0.0000531 AC: 8 AN: 150584 Hom.: 0 Cov.: 30 AF XY: 0.0000681 AC XY: 5 AN XY: 73418

African (AFR) AF: 0.00 AC: 0 AN: 40888

American (AMR) AF: 0.0000667 AC: 1 AN: 14986

Ashkenazi Jewish (ASJ) AF: 0.000290 AC: 1 AN: 3454

East Asian (EAS) AF: 0.00 AC: 0 AN: 5148

South Asian (SAS) AF: 0.000216 AC: 1 AN: 4634

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10438

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

European-Non Finnish (NFE) AF: 0.0000738 AC: 5 AN: 67764

Other (OTH) AF: 0.00 AC: 0 AN: 2072

Alfa AF: 0.000304 Hom.: 0

Bravo AF: 0.0000491

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
CADD	Benign	17
DANN	Benign	0.90
PhyloP100		2.6

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

Other links and lift over

dbSNP: rs397517864; hg19: chr18-44065129;