chr18-46529070-T-C

Variant names:

• chr18-46529070-T-C
• rs1450425
• NM_001384474.1:c.4530+107A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001384474.1(LOXHD1):​c.4530+107A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.712 in 1,356,964 control chromosomes in the GnomAD database, including 346,192 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.66 (33931 hom., cov: 29)
  • Exomes 𝑓: 0.72 (312261 hom.)
• Consequence: LOXHD1 NM_001384474.1 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -1.88
• Publications: 8 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BP6: Variant 18-46529070-T-C is Benign according to our data. Variant chr18-46529070-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 191090.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.727 is higher than 0.05.

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.4530+107A>G		intron	N/A	NP_001371403.1	A0A2R8Y7K4
	LOXHD1	NM_144612.7		c.4530+107A>G		intron	N/A	NP_653213.6
	LOXHD1	NM_001145472.3		c.1197+107A>G		intron	N/A	NP_001138944.1	Q8IVV2-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LOXHD1	ENST00000642948.1	MANE Select	c.4530+107A>G		intron	N/A	ENSP00000496347.1	A0A2R8Y7K4
	LOXHD1	ENST00000300591.11	TSL:1	c.1197+107A>G		intron	N/A	ENSP00000300591.6	Q8IVV2-3
	LOXHD1	ENST00000579038.6	TSL:1	c.909+107A>G		intron	N/A	ENSP00000463285.1	J3QKX9

Frequencies

GnomAD3 genomes AF: 0.663 AC: 100528 AN: 151542 Hom.: 33920 Cov.: 29

Gnomad AFR AF: 0.547

Gnomad AMI AF: 0.384

Gnomad AMR AF: 0.648

Gnomad ASJ AF: 0.708

Gnomad EAS AF: 0.591

Gnomad SAS AF: 0.676

Gnomad FIN AF: 0.734

Gnomad MID AF: 0.680

Gnomad NFE AF: 0.732

Gnomad OTH AF: 0.669

GnomAD4 exome AF: 0.718 AC: 865381 AN: 1205304 Hom.: 312261 AF XY: 0.718 AC XY: 428587 AN XY: 596972

African (AFR) AF: 0.539 AC: 15084 AN: 28006

American (AMR) AF: 0.642 AC: 21029 AN: 32730

Ashkenazi Jewish (ASJ) AF: 0.701 AC: 14926 AN: 21302

East Asian (EAS) AF: 0.620 AC: 21382 AN: 34508

South Asian (SAS) AF: 0.680 AC: 46078 AN: 67712

European-Finnish (FIN) AF: 0.733 AC: 34822 AN: 47492

Middle Eastern (MID) AF: 0.689 AC: 2657 AN: 3856

European-Non Finnish (NFE) AF: 0.733 AC: 673416 AN: 918692

Other (OTH) AF: 0.706 AC: 35987 AN: 51006

GnomAD4 genome AF: 0.663 AC: 100580 AN: 151660 Hom.: 33931 Cov.: 29 AF XY: 0.662 AC XY: 49070 AN XY: 74086

African (AFR) AF: 0.547 AC: 22567 AN: 41276

American (AMR) AF: 0.648 AC: 9895 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.708 AC: 2457 AN: 3470

East Asian (EAS) AF: 0.590 AC: 3023 AN: 5122

South Asian (SAS) AF: 0.676 AC: 3251 AN: 4812

European-Finnish (FIN) AF: 0.734 AC: 7699 AN: 10482

Middle Eastern (MID) AF: 0.680 AC: 200 AN: 294

European-Non Finnish (NFE) AF: 0.732 AC: 49731 AN: 67920

Other (OTH) AF: 0.668 AC: 1408 AN: 2108

Alfa AF: 0.711 Hom.: 64543

Bravo AF: 0.650

Asia WGS AF: 0.660 AC: 2298 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.43
DANN	Benign	0.41
PhyloP100		-1.9
Mutation Taster		=100/0	polymorphism (auto)

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: rs1450425; hg19: chr18-44109033; COSMIC: COSV56072333; COSMIC: COSV56072333;