rs376539851

Variant names:

• chr18-46566443-G-A
• rs376539851
• NM_001384474.1:c.2251C>T

Your query was ambiguous. Multiple possible variants found:

• chr18-46566443-G-A
• chr18-46566443-G-T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_001384474.1(LOXHD1):​c.2251C>T​(p.Arg751Trp) variant causes a missense change. The variant allele was found at a frequency of 0.000818 in 1,549,294 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. R751R) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00056 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00085 (1 hom.)
• Consequence: LOXHD1 NM_001384474.1 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:9
• Conservation: PhyloP100: 4.68
• 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, 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: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.090696424).

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.2251C>T	p.Arg751Trp	missense	Exon 17 of 41	NP_001371403.1
	LOXHD1	NM_144612.7		c.2251C>T	p.Arg751Trp	missense	Exon 17 of 40	NP_653213.6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LOXHD1	ENST00000642948.1	MANE Select	c.2251C>T	p.Arg751Trp	missense	Exon 17 of 41	ENSP00000496347.1
	LOXHD1	ENST00000536736.5	TSL:5	c.2251C>T	p.Arg751Trp	missense	Exon 17 of 40	ENSP00000444586.1
	LOXHD1	ENST00000441551.6	TSL:5	c.2251C>T	p.Arg751Trp	missense	Exon 17 of 39	ENSP00000387621.2

Frequencies

GnomAD3 genomes AF: 0.000559 AC: 85 AN: 152172 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000193

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000524

Gnomad ASJ AF: 0.00231

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000853

Gnomad OTH AF: 0.000958

GnomAD2 exomes AF: 0.000538 AC: 84 AN: 156082 AF XY: 0.000582

Gnomad AFR exome AF: 0.000231

Gnomad AMR exome AF: 0.000445

Gnomad ASJ exome AF: 0.00130

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000672

Gnomad NFE exome AF: 0.000888

Gnomad OTH exome AF: 0.000900

GnomAD4 exome AF: 0.000847 AC: 1183 AN: 1397004 Hom.: 1 Cov.: 31 AF XY: 0.000808 AC XY: 557 AN XY: 689058

African (AFR) AF: 0.000127 AC: 4 AN: 31596

American (AMR) AF: 0.000420 AC: 15 AN: 35702

Ashkenazi Jewish (ASJ) AF: 0.00115 AC: 29 AN: 25182

East Asian (EAS) AF: 0.000112 AC: 4 AN: 35732

South Asian (SAS) AF: 0.0000379 AC: 3 AN: 79226

European-Finnish (FIN) AF: 0.0000638 AC: 3 AN: 47022

Middle Eastern (MID) AF: 0.000176 AC: 1 AN: 5698

European-Non Finnish (NFE) AF: 0.00100 AC: 1083 AN: 1078866

Other (OTH) AF: 0.000707 AC: 41 AN: 57980

GnomAD4 genome AF: 0.000558 AC: 85 AN: 152290 Hom.: 0 Cov.: 33 AF XY: 0.000349 AC XY: 26 AN XY: 74466

African (AFR) AF: 0.000192 AC: 8 AN: 41560

American (AMR) AF: 0.000523 AC: 8 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00231 AC: 8 AN: 3470

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

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

European-Non Finnish (NFE) AF: 0.000853 AC: 58 AN: 68016

Other (OTH) AF: 0.000948 AC: 2 AN: 2110

Alfa AF: 0.000491 Hom.: 0

Bravo AF: 0.000589

TwinsUK AF: 0.00189 AC: 7

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00145 AC: 2

ESP6500EA AF: 0.00251 AC: 8

ExAC AF: 0.000803 AC: 21

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.69
BayesDel_addAF	Benign	-0.036	T
BayesDel_noAF	Uncertain	0.11
CADD	Pathogenic	27
DANN	Uncertain	0.98
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.97	D
M_CAP	Benign	0.064	D
MetaRNN	Benign	0.091	T
MetaSVM	Uncertain	-0.18	T
PhyloP100		4.7
PrimateAI	Uncertain	0.57	T
PROVEAN	Pathogenic	-5.5	D
REVEL	Uncertain	0.57
Sift	Uncertain	0.0030	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.79
MVP		0.41
ClinPred		0.22	T
GERP RS		3.9
Varity_R		0.27
gMVP		0.81
Mutation Taster		=58/42	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: rs376539851; hg19: chr18-44146406; COSMIC: COSV59661020;