rs35088381

Variant names:

• chr18-46577783-C-A
• rs35088381
• NM_001384474.1:c.1894G>T

Your query was ambiguous. Multiple possible variants found:

• chr18-46577783-C-A
• chr18-46577783-C-T

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.1894G>T​(p.Gly632Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0141 in 1,551,590 control chromosomes in the GnomAD database, including 267 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. G632S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.015 (22 hom., cov: 32)
  • Exomes 𝑓: 0.014 (245 hom.)
• Consequence: LOXHD1 NM_001384474.1 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:7
• Conservation: PhyloP100: 7.84
• Publications: 11 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=0.014604986).
• BP6: Variant 18-46577783-C-A is Benign according to our data. Variant chr18-46577783-C-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 47923.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.0154 (2338/152196) while in subpopulation SAS AF = 0.0293 (141/4814). AF 95% confidence interval is 0.0254. There are 22 homozygotes in GnomAd4. There are 1113 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 22 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.1894G>T	p.Gly632Cys	missense	Exon 14 of 41	NP_001371403.1	A0A2R8Y7K4
	LOXHD1	NM_144612.7		c.1894G>T	p.Gly632Cys	missense	Exon 14 of 40	NP_653213.6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LOXHD1	ENST00000642948.1	MANE Select	c.1894G>T	p.Gly632Cys	missense	Exon 14 of 41	ENSP00000496347.1	A0A2R8Y7K4
	LOXHD1	ENST00000536736.5	TSL:5	c.1894G>T	p.Gly632Cys	missense	Exon 14 of 40	ENSP00000444586.1	F5GZB4
	LOXHD1	ENST00000441551.6	TSL:5	c.1894G>T	p.Gly632Cys	missense	Exon 14 of 39	ENSP00000387621.2	Q8IVV2-1

Frequencies

GnomAD3 genomes AF: 0.0153 AC: 2334 AN: 152078 Hom.: 23 Cov.: 32

Gnomad AFR AF: 0.0178

Gnomad AMI AF: 0.0186

Gnomad AMR AF: 0.0148

Gnomad ASJ AF: 0.0476

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0295

Gnomad FIN AF: 0.00499

Gnomad MID AF: 0.0380

Gnomad NFE AF: 0.0139

Gnomad OTH AF: 0.0163

GnomAD2 exomes AF: 0.0164 AC: 2600 AN: 158092 AF XY: 0.0179

Gnomad AFR exome AF: 0.0191

Gnomad AMR exome AF: 0.0119

Gnomad ASJ exome AF: 0.0456

Gnomad EAS exome AF: 0.000265

Gnomad FIN exome AF: 0.00308

Gnomad NFE exome AF: 0.0134

Gnomad OTH exome AF: 0.0186

GnomAD4 exome AF: 0.0139 AC: 19482 AN: 1399394 Hom.: 245 Cov.: 31 AF XY: 0.0147 AC XY: 10151 AN XY: 690210

African (AFR) AF: 0.0195 AC: 617 AN: 31596

American (AMR) AF: 0.0124 AC: 444 AN: 35704

Ashkenazi Jewish (ASJ) AF: 0.0429 AC: 1081 AN: 25182

East Asian (EAS) AF: 0.000168 AC: 6 AN: 35738

South Asian (SAS) AF: 0.0350 AC: 2774 AN: 79232

European-Finnish (FIN) AF: 0.00418 AC: 206 AN: 49276

Middle Eastern (MID) AF: 0.0381 AC: 217 AN: 5696

European-Non Finnish (NFE) AF: 0.0121 AC: 13078 AN: 1078968

Other (OTH) AF: 0.0183 AC: 1059 AN: 58002

GnomAD4 genome AF: 0.0154 AC: 2338 AN: 152196 Hom.: 22 Cov.: 32 AF XY: 0.0150 AC XY: 1113 AN XY: 74414

African (AFR) AF: 0.0179 AC: 743 AN: 41530

American (AMR) AF: 0.0148 AC: 226 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.0476 AC: 165 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.0293 AC: 141 AN: 4814

European-Finnish (FIN) AF: 0.00499 AC: 53 AN: 10612

Middle Eastern (MID) AF: 0.0374 AC: 11 AN: 294

European-Non Finnish (NFE) AF: 0.0139 AC: 947 AN: 67996

Other (OTH) AF: 0.0166 AC: 35 AN: 2110

Alfa AF: 0.0131 Hom.: 14

Bravo AF: 0.0157

TwinsUK AF: 0.0111 AC: 41

ALSPAC AF: 0.0138 AC: 53

ESP6500AA AF: 0.0152 AC: 21

ESP6500EA AF: 0.0141 AC: 45

ExAC AF: 0.0220 AC: 579

Asia WGS AF: 0.0130 AC: 44 AN: 3478

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.40
BayesDel_addAF	Benign	-0.0064	T
BayesDel_noAF	Pathogenic	0.24
CADD	Uncertain	23
DANN	Benign	0.96
Eigen	Uncertain	0.45
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.88	D
MetaRNN	Benign	0.015	T
MetaSVM	Uncertain	0.067	D
PhyloP100		7.8
PrimateAI	Uncertain	0.59	T
PROVEAN	Pathogenic	-6.8	D
REVEL	Uncertain	0.53
Sift	Uncertain	0.0030	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.62
ClinPred		0.047	T
GERP RS		4.8
Varity_R		0.30
gMVP		0.82
Mutation Taster		=60/40	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: rs35088381; hg19: chr18-44157746;