rs118174674

Variant names:

• chr18-46557437-C-T
• rs118174674
• NM_001384474.1:c.3269G>A

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 2P and 13B. PM5 BP4_Strong BP6 BS1 BS2

The NM_001384474.1(LOXHD1):​c.3269G>A​(p.Arg1090Gln) variant causes a missense change. The variant allele was found at a frequency of 0.0175 in 1,552,130 control chromosomes in the GnomAD database, including 264 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1090W) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.013 (19 hom., cov: 32)
  • Exomes 𝑓: 0.018 (245 hom.)
• Consequence: LOXHD1 NM_001384474.1 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:7 O:1
• Conservation: PhyloP100: 5.03
• Publications: 14 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, PanelApp Australia, 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 -11 ACMG points.

• PM5: Other missense variant is known to change same aminoacid residue: Variant chr18-46557438-G-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 3382632.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.013051391).
• BP6: Variant 18-46557437-C-T is Benign according to our data. Variant chr18-46557437-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 47933.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0133 (2031/152252) while in subpopulation NFE AF = 0.0219 (1488/68022). AF 95% confidence interval is 0.021. There are 19 homozygotes in GnomAd4. There are 910 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 19 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.3269G>A	p.Arg1090Gln	missense	Exon 21 of 41	NP_001371403.1	A0A2R8Y7K4
	LOXHD1	NM_144612.7		c.3269G>A	p.Arg1090Gln	missense	Exon 21 of 40	NP_653213.6
	LOXHD1	NM_001145472.3		c.-65G>A		5_prime_UTR	Exon 3 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.3269G>A	p.Arg1090Gln	missense	Exon 21 of 41	ENSP00000496347.1	A0A2R8Y7K4
	LOXHD1	ENST00000300591.11	TSL:1	c.-65G>A		5_prime_UTR	Exon 3 of 24	ENSP00000300591.6	Q8IVV2-3
	LOXHD1	ENST00000536736.5	TSL:5	c.3269G>A	p.Arg1090Gln	missense	Exon 21 of 40	ENSP00000444586.1	F5GZB4

Frequencies

GnomAD3 genomes AF: 0.0134 AC: 2031 AN: 152134 Hom.: 19 Cov.: 32

Gnomad AFR AF: 0.00304

Gnomad AMI AF: 0.0186

Gnomad AMR AF: 0.0154

Gnomad ASJ AF: 0.0101

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00207

Gnomad FIN AF: 0.00773

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.0219

Gnomad OTH AF: 0.0163

GnomAD2 exomes AF: 0.0122 AC: 1954 AN: 160138 AF XY: 0.0118

Gnomad AFR exome AF: 0.00224

Gnomad AMR exome AF: 0.00888

Gnomad ASJ exome AF: 0.0104

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00719

Gnomad NFE exome AF: 0.0224

Gnomad OTH exome AF: 0.0140

GnomAD4 exome AF: 0.0179 AC: 25077 AN: 1399878 Hom.: 245 Cov.: 33 AF XY: 0.0177 AC XY: 12249 AN XY: 690416

African (AFR) AF: 0.00241 AC: 76 AN: 31600

American (AMR) AF: 0.0106 AC: 380 AN: 35708

Ashkenazi Jewish (ASJ) AF: 0.0105 AC: 264 AN: 25182

East Asian (EAS) AF: 0.00 AC: 0 AN: 35738

South Asian (SAS) AF: 0.00273 AC: 216 AN: 79236

European-Finnish (FIN) AF: 0.00818 AC: 405 AN: 49508

Middle Eastern (MID) AF: 0.00982 AC: 56 AN: 5700

European-Non Finnish (NFE) AF: 0.0211 AC: 22812 AN: 1079070

Other (OTH) AF: 0.0149 AC: 868 AN: 58136

GnomAD4 genome AF: 0.0133 AC: 2031 AN: 152252 Hom.: 19 Cov.: 32 AF XY: 0.0122 AC XY: 910 AN XY: 74444

African (AFR) AF: 0.00303 AC: 126 AN: 41528

American (AMR) AF: 0.0154 AC: 235 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.0101 AC: 35 AN: 3468

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5182

South Asian (SAS) AF: 0.00208 AC: 10 AN: 4818

European-Finnish (FIN) AF: 0.00773 AC: 82 AN: 10612

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.0219 AC: 1488 AN: 68022

Other (OTH) AF: 0.0161 AC: 34 AN: 2112

Alfa AF: 0.0187 Hom.: 96

Bravo AF: 0.0141

TwinsUK AF: 0.0197 AC: 73

ALSPAC AF: 0.0252 AC: 97

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.0192 AC: 61

ExAC AF: 0.00831 AC: 240

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	2	Autosomal recessive nonsyndromic hearing loss 77 (4)
-	-	3	not specified (3)
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.30
BayesDel_addAF	Benign	-0.035	T
BayesDel_noAF	Pathogenic	0.20
CADD	Pathogenic	26
DANN	Uncertain	0.99
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.97	D
MetaRNN	Benign	0.013	T
MetaSVM	Benign	-0.55	T
PhyloP100		5.0
PrimateAI	Uncertain	0.52	T
PROVEAN	Uncertain	-2.5	D
REVEL	Uncertain	0.52
Sift	Uncertain	0.014	D
Sift4G	Uncertain	0.010	D
Polyphen		1.0	D
Vest4		0.60
ClinPred		0.037	T
GERP RS		5.2
Varity_R		0.11
gMVP		0.71
Mutation Taster		=277/23	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs118174674; hg19: chr18-44137400; COSMIC: COSV107364091; COSMIC: COSV107364091;