chr18-46485102-G-A

Variant names:

• chr18-46485102-G-A
• rs146200756
• NM_001384474.1:c.6099C>T

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP6 BS1 BS2

The NM_001384474.1(LOXHD1):​c.6099C>T​(p.Asn2033Asn) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00189 in 1,549,766 control chromosomes in the GnomAD database, including 32 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0014 (4 hom., cov: 30)
  • Exomes 𝑓: 0.0019 (28 hom.)
• Consequence: LOXHD1 NM_001384474.1 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:5
• Conservation: PhyloP100: -0.139
• Publications: 3 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 -9 ACMG points.

• BP6: Variant 18-46485102-G-A is Benign according to our data. Variant chr18-46485102-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 178392.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00144 (217/150330) while in subpopulation SAS AF = 0.0128 (59/4626). AF 95% confidence interval is 0.0102. There are 4 homozygotes in GnomAd4. There are 119 alleles in the male GnomAd4 subpopulation. Median coverage is 30. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 4 AD,AR 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.6099C>T	p.Asn2033Asn	synonymous	Exon 39 of 41	NP_001371403.1	A0A2R8Y7K4
	LOXHD1	NM_144612.7		c.5913C>T	p.Asn1971Asn	synonymous	Exon 38 of 40	NP_653213.6
	LOXHD1	NM_001145472.3		c.2766C>T	p.Asn922Asn	synonymous	Exon 21 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.6099C>T	p.Asn2033Asn	synonymous	Exon 39 of 41	ENSP00000496347.1	A0A2R8Y7K4
	LOXHD1	ENST00000300591.11	TSL:1	c.2766C>T	p.Asn922Asn	synonymous	Exon 21 of 24	ENSP00000300591.6	Q8IVV2-3
	LOXHD1	ENST00000579038.6	TSL:1	c.2478C>T	p.Asn826Asn	synonymous	Exon 19 of 22	ENSP00000463285.1	J3QKX9

Frequencies

GnomAD3 genomes AF: 0.00142 AC: 213 AN: 150212 Hom.: 3 Cov.: 30

Gnomad AFR AF: 0.000197

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000669

Gnomad ASJ AF: 0.000290

Gnomad EAS AF: 0.00802

Gnomad SAS AF: 0.0119

Gnomad FIN AF: 0.000290

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00136

Gnomad OTH AF: 0.00145

GnomAD2 exomes AF: 0.00342 AC: 540 AN: 158032 AF XY: 0.00407

Gnomad AFR exome AF: 0.000244

Gnomad AMR exome AF: 0.000810

Gnomad ASJ exome AF: 0.000822

Gnomad EAS exome AF: 0.0127

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00154

Gnomad OTH exome AF: 0.00290

GnomAD4 exome AF: 0.00193 AC: 2706 AN: 1399436 Hom.: 28 Cov.: 35 AF XY: 0.00226 AC XY: 1561 AN XY: 690234

African (AFR) AF: 0.000253 AC: 8 AN: 31598

American (AMR) AF: 0.000840 AC: 30 AN: 35696

Ashkenazi Jewish (ASJ) AF: 0.000596 AC: 15 AN: 25170

East Asian (EAS) AF: 0.00521 AC: 186 AN: 35734

South Asian (SAS) AF: 0.0113 AC: 897 AN: 79182

European-Finnish (FIN) AF: 0.000142 AC: 7 AN: 49464

Middle Eastern (MID) AF: 0.00930 AC: 53 AN: 5696

European-Non Finnish (NFE) AF: 0.00126 AC: 1362 AN: 1078790

Other (OTH) AF: 0.00255 AC: 148 AN: 58106

GnomAD4 genome AF: 0.00144 AC: 217 AN: 150330 Hom.: 4 Cov.: 30 AF XY: 0.00162 AC XY: 119 AN XY: 73236

African (AFR) AF: 0.000196 AC: 8 AN: 40788

American (AMR) AF: 0.000668 AC: 10 AN: 14962

Ashkenazi Jewish (ASJ) AF: 0.000290 AC: 1 AN: 3450

East Asian (EAS) AF: 0.00804 AC: 41 AN: 5100

South Asian (SAS) AF: 0.0128 AC: 59 AN: 4626

European-Finnish (FIN) AF: 0.000290 AC: 3 AN: 10338

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 288

European-Non Finnish (NFE) AF: 0.00136 AC: 92 AN: 67782

Other (OTH) AF: 0.00144 AC: 3 AN: 2090

Alfa AF: 0.00144 Hom.: 0

Bravo AF: 0.00108

Asia WGS AF: 0.00606 AC: 21 AN: 3478

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	1	1	Autosomal recessive nonsyndromic hearing loss 77 (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.37
CADD	Benign	0.98
DANN	Benign	0.80
PhyloP100		-0.14
Mutation Taster		=98/2	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.28		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.28		Position offset: 49

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

Other links and lift over

dbSNP: rs146200756; hg19: chr18-44065065; COSMIC: COSV56070150;