rs370616818

Variant names:

• chr18-46560120-G-A
• rs370616818
• NM_001384474.1:c.3024C>T

Your query was ambiguous. Multiple possible variants found:

• chr18-46560120-G-A
• chr18-46560120-G-T

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP6 BP7 BS2

The NM_001384474.1(LOXHD1):​c.3024C>T​(p.Val1008Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00162 in 1,270,194 control chromosomes in the GnomAD database, including 3 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. V1008V) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0013 (0 hom., cov: 30)
  • Exomes 𝑓: 0.0016 (3 hom.)
• Consequence: LOXHD1 NM_001384474.1 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:7
• Conservation: PhyloP100: -0.774
• Publications: 1 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.

• BP6: Variant 18-46560120-G-A is Benign according to our data. Variant chr18-46560120-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 227515.
• BP7: Synonymous conserved (PhyloP=-0.774 with no splicing effect.
• BS2: High Homozygotes in GnomAdExome4 at 3 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.3024C>T	p.Val1008Val	synonymous	Exon 19 of 41	NP_001371403.1	A0A2R8Y7K4
	LOXHD1	NM_144612.7		c.3024C>T	p.Val1008Val	synonymous	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.3024C>T	p.Val1008Val	synonymous	Exon 19 of 41	ENSP00000496347.1	A0A2R8Y7K4
	LOXHD1	ENST00000536736.5	TSL:5	c.3024C>T	p.Val1008Val	synonymous	Exon 19 of 40	ENSP00000444586.1	F5GZB4
	LOXHD1	ENST00000441551.6	TSL:5	c.2599-2631C>T		intron	N/A	ENSP00000387621.2	Q8IVV2-1

Frequencies

GnomAD3 genomes AF: 0.00132 AC: 159 AN: 120512 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.000471

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000576

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000292

Gnomad FIN AF: 0.00326

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00193

Gnomad OTH AF: 0.00120

GnomAD2 exomes AF: 0.000990 AC: 156 AN: 157646 AF XY: 0.00113

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000364

Gnomad ASJ exome AF: 0.000118

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00131

Gnomad NFE exome AF: 0.00202

Gnomad OTH exome AF: 0.000449

GnomAD4 exome AF: 0.00165 AC: 1894 AN: 1149632 Hom.: 3 Cov.: 38 AF XY: 0.00166 AC XY: 930 AN XY: 561842

African (AFR) AF: 0.000246 AC: 6 AN: 24380

American (AMR) AF: 0.000461 AC: 13 AN: 28224

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 15960

East Asian (EAS) AF: 0.00 AC: 0 AN: 13026

South Asian (SAS) AF: 0.0000260 AC: 2 AN: 76810

European-Finnish (FIN) AF: 0.00158 AC: 45 AN: 28564

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4384

European-Non Finnish (NFE) AF: 0.00194 AC: 1778 AN: 916820

Other (OTH) AF: 0.00121 AC: 50 AN: 41464

GnomAD4 genome AF: 0.00132 AC: 159 AN: 120562 Hom.: 0 Cov.: 30 AF XY: 0.00138 AC XY: 77 AN XY: 55668

African (AFR) AF: 0.000470 AC: 15 AN: 31900

American (AMR) AF: 0.000574 AC: 5 AN: 8704

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3258

East Asian (EAS) AF: 0.00 AC: 0 AN: 3532

South Asian (SAS) AF: 0.000293 AC: 1 AN: 3418

European-Finnish (FIN) AF: 0.00326 AC: 16 AN: 4908

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 176

European-Non Finnish (NFE) AF: 0.00193 AC: 120 AN: 62126

Other (OTH) AF: 0.00119 AC: 2 AN: 1678

Alfa AF: 0.00152 Hom.: 0

Bravo AF: 0.000990

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	2	Autosomal recessive nonsyndromic hearing loss 77 (3)
-	-	3	not provided (3)
-	-	1	LOXHD1-related disorder (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.28
CADD	Benign	3.1
DANN	Benign	0.69
PhyloP100		-0.77
Mutation Taster		=99/1	polymorphism

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: rs370616818; hg19: chr18-44140083;