rs112618498

Variant names:

• chr18-46639670-G-A
• rs112618498
• NM_001384474.1:c.457C>T

Your query was ambiguous. Multiple possible variants found:

• chr18-46639670-G-A
• chr18-46639670-G-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.457C>T​(p.Arg153Cys) variant causes a missense change. The variant allele was found at a frequency of 0.000755 in 1,551,722 control chromosomes in the GnomAD database, including 8 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. R153H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0038 (5 hom., cov: 32)
  • Exomes 𝑓: 0.00042 (3 hom.)
• Consequence: LOXHD1 NM_001384474.1 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:5
• Conservation: PhyloP100: 4.71
• 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: G2P, PanelApp Australia, Labcorp Genetics (formerly Invitae), Ambry Genetics
• 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=0.007599801).
• BP6: Variant 18-46639670-G-A is Benign according to our data. Variant chr18-46639670-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 47938.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00383 (584/152314) while in subpopulation AFR AF = 0.0136 (564/41568). AF 95% confidence interval is 0.0126. There are 5 homozygotes in GnomAd4. There are 258 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 5 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.457C>T	p.Arg153Cys	missense	Exon 4 of 41	NP_001371403.1
	LOXHD1	NM_144612.7		c.457C>T	p.Arg153Cys	missense	Exon 4 of 40	NP_653213.6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LOXHD1	ENST00000642948.1	MANE Select	c.457C>T	p.Arg153Cys	missense	Exon 4 of 41	ENSP00000496347.1
	LOXHD1	ENST00000536736.5	TSL:5	c.457C>T	p.Arg153Cys	missense	Exon 4 of 40	ENSP00000444586.1
	LOXHD1	ENST00000441551.6	TSL:5	c.457C>T	p.Arg153Cys	missense	Exon 4 of 39	ENSP00000387621.2

Frequencies

GnomAD3 genomes AF: 0.00382 AC: 582 AN: 152196 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.0136

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000720

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.000862 AC: 135 AN: 156568 AF XY: 0.000566

Gnomad AFR exome AF: 0.0146

Gnomad AMR exome AF: 0.000486

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000595

Gnomad NFE exome AF: 0.0000660

Gnomad OTH exome AF: 0.000228

GnomAD4 exome AF: 0.000419 AC: 587 AN: 1399408 Hom.: 3 Cov.: 31 AF XY: 0.000354 AC XY: 244 AN XY: 690220

African (AFR) AF: 0.0150 AC: 473 AN: 31598

American (AMR) AF: 0.000336 AC: 12 AN: 35702

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 35736

South Asian (SAS) AF: 0.0000252 AC: 2 AN: 79236

European-Finnish (FIN) AF: 0.000101 AC: 5 AN: 49280

Middle Eastern (MID) AF: 0.000351 AC: 2 AN: 5698

European-Non Finnish (NFE) AF: 0.0000287 AC: 31 AN: 1078968

Other (OTH) AF: 0.00107 AC: 62 AN: 58008

GnomAD4 genome AF: 0.00383 AC: 584 AN: 152314 Hom.: 5 Cov.: 32 AF XY: 0.00346 AC XY: 258 AN XY: 74460

African (AFR) AF: 0.0136 AC: 564 AN: 41568

American (AMR) AF: 0.000719 AC: 11 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4824

European-Finnish (FIN) AF: 0.0000942 AC: 1 AN: 10616

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

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68034

Other (OTH) AF: 0.00189 AC: 4 AN: 2114

Alfa AF: 0.00394 Hom.: 1

Bravo AF: 0.00445

ESP6500AA AF: 0.0130 AC: 18

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00167 AC: 43

Asia WGS AF: 0.00173 AC: 6 AN: 3478

ClinVar

ClinVar submissions as Germline

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
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.25
CADD	Pathogenic	27
DANN	Uncertain	0.99
Eigen	Uncertain	0.47
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.89	D
MetaRNN	Benign	0.0076	T
MetaSVM	Benign	-1.0	T
PhyloP100		4.7
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-1.7	N
REVEL	Benign	0.18
Sift	Uncertain	0.020	D
Sift4G	Uncertain	0.013	D
Polyphen		1.0	D
Vest4		0.39
MVP		0.28
ClinPred		0.032	T
GERP RS		5.8
Varity_R		0.16
gMVP		0.58
Mutation Taster		=94/6	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: rs112618498; hg19: chr18-44219633;