rs35007621

Variant names:

• chr18-46579697-A-G
• rs35007621
• NM_001384474.1:c.1742T>C

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001384474.1(LOXHD1):​c.1742T>C​(p.Val581Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00158 in 1,551,732 control chromosomes in the GnomAD database, including 44 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0087 (30 hom., cov: 33)
  • Exomes 𝑓: 0.00081 (14 hom.)
• Consequence: LOXHD1 NM_001384474.1 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:5
• Conservation: PhyloP100: 3.32
• 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009079218).
• BP6: Variant 18-46579697-A-G is Benign according to our data. Variant chr18-46579697-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 47920.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00874 (1331/152264) while in subpopulation AFR AF = 0.031 (1286/41532). AF 95% confidence interval is 0.0296. There are 30 homozygotes in GnomAd4. There are 635 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 30 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.1742T>C	p.Val581Ala	missense	Exon 13 of 41	NP_001371403.1	A0A2R8Y7K4
	LOXHD1	NM_144612.7		c.1742T>C	p.Val581Ala	missense	Exon 13 of 40	NP_653213.6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LOXHD1	ENST00000642948.1	MANE Select	c.1742T>C	p.Val581Ala	missense	Exon 13 of 41	ENSP00000496347.1	A0A2R8Y7K4
	LOXHD1	ENST00000536736.5	TSL:5	c.1742T>C	p.Val581Ala	missense	Exon 13 of 40	ENSP00000444586.1	F5GZB4
	LOXHD1	ENST00000441551.6	TSL:5	c.1742T>C	p.Val581Ala	missense	Exon 13 of 39	ENSP00000387621.2	Q8IVV2-1

Frequencies

GnomAD3 genomes AF: 0.00872 AC: 1326 AN: 152146 Hom.: 29 Cov.: 33

Gnomad AFR AF: 0.0309

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00229

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00430

GnomAD2 exomes AF: 0.00158 AC: 250 AN: 158692 AF XY: 0.00117

Gnomad AFR exome AF: 0.0263

Gnomad AMR exome AF: 0.000606

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000893

GnomAD4 exome AF: 0.000805 AC: 1127 AN: 1399468 Hom.: 14 Cov.: 31 AF XY: 0.000677 AC XY: 467 AN XY: 690242

African (AFR) AF: 0.0318 AC: 1006 AN: 31598

American (AMR) AF: 0.000924 AC: 33 AN: 35704

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25182

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

South Asian (SAS) AF: 0.0000126 AC: 1 AN: 79236

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49298

Middle Eastern (MID) AF: 0.000702 AC: 4 AN: 5698

European-Non Finnish (NFE) AF: 0.00000463 AC: 5 AN: 1078986

Other (OTH) AF: 0.00134 AC: 78 AN: 58028

GnomAD4 genome AF: 0.00874 AC: 1331 AN: 152264 Hom.: 30 Cov.: 33 AF XY: 0.00853 AC XY: 635 AN XY: 74460

African (AFR) AF: 0.0310 AC: 1286 AN: 41532

American (AMR) AF: 0.00229 AC: 35 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

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

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68014

Other (OTH) AF: 0.00426 AC: 9 AN: 2114

Alfa AF: 0.00633 Hom.: 14

Bravo AF: 0.00948

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.0267 AC: 37

ESP6500EA AF: 0.000314 AC: 1

ExAC AF: 0.00271 AC: 75

Asia WGS AF: 0.000866 AC: 3 AN: 3478

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)
-	-	2	not provided (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	17
DANN	Benign	0.95
Eigen	Benign	-0.58
Eigen_PC	Benign	-0.34
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Benign	0.68	T
MetaRNN	Benign	0.0091	T
MetaSVM	Benign	-1.1	T
PhyloP100		3.3
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-0.92	N
REVEL	Benign	0.048
Sift	Benign	0.63	T
Sift4G	Benign	0.41	T
Polyphen		0.0020	B
Vest4		0.22
MVP		0.088
ClinPred		0.016	T
GERP RS		2.8
Varity_R		0.043
gMVP		0.20
Mutation Taster		=92/8	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: rs35007621; hg19: chr18-44159660; COSMIC: COSV99046479;