rs191697915

Variant names:

• chr18-46610813-T-C
• rs191697915
• NM_001384474.1:c.722A>G

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_001384474.1(LOXHD1):​c.722A>G​(p.Asn241Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000416 in 1,551,698 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N241K) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00042 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00042 (1 hom.)
• Consequence: LOXHD1 NM_001384474.1 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:8 B:1
• Conservation: PhyloP100: 7.88
• Publications: 0 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: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.032109827).

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LOXHD1	NM_001384474.1	MANE Select	c.722A>G	p.Asn241Ser	missense	Exon 6 of 41	NP_001371403.1
	LOXHD1	NM_144612.7		c.722A>G	p.Asn241Ser	missense	Exon 6 of 40	NP_653213.6

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LOXHD1	ENST00000642948.1	MANE Select	c.722A>G	p.Asn241Ser	missense	Exon 6 of 41	ENSP00000496347.1
	LOXHD1	ENST00000536736.5	TSL:5	c.722A>G	p.Asn241Ser	missense	Exon 6 of 40	ENSP00000444586.1
	LOXHD1	ENST00000441551.6	TSL:5	c.722A>G	p.Asn241Ser	missense	Exon 6 of 39	ENSP00000387621.2

Frequencies

GnomAD3 genomes AF: 0.000420 AC: 64 AN: 152208 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00183

Gnomad ASJ AF: 0.000577

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000397

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000415 AC: 65 AN: 156600 AF XY: 0.000386

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00150

Gnomad ASJ exome AF: 0.000706

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000297

Gnomad OTH exome AF: 0.000910

GnomAD4 exome AF: 0.000415 AC: 581 AN: 1399372 Hom.: 1 Cov.: 30 AF XY: 0.000391 AC XY: 270 AN XY: 690178

African (AFR) AF: 0.0000317 AC: 1 AN: 31594

American (AMR) AF: 0.00179 AC: 64 AN: 35698

Ashkenazi Jewish (ASJ) AF: 0.000794 AC: 20 AN: 25180

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 79228

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49280

Middle Eastern (MID) AF: 0.000176 AC: 1 AN: 5696

European-Non Finnish (NFE) AF: 0.000440 AC: 475 AN: 1078952

Other (OTH) AF: 0.000345 AC: 20 AN: 58006

GnomAD4 genome AF: 0.000420 AC: 64 AN: 152326 Hom.: 0 Cov.: 32 AF XY: 0.000483 AC XY: 36 AN XY: 74476

African (AFR) AF: 0.000144 AC: 6 AN: 41570

American (AMR) AF: 0.00183 AC: 28 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.000577 AC: 2 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4814

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

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

European-Non Finnish (NFE) AF: 0.000397 AC: 27 AN: 68040

Other (OTH) AF: 0.000473 AC: 1 AN: 2114

Alfa AF: 0.000409 Hom.: 0

Bravo AF: 0.000476

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000519 AC: 2

ExAC AF: 0.000194 AC: 5

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	4	-	not provided (4)
-	2	-	Autosomal recessive nonsyndromic hearing loss 77 (2)
-	1	-	Inborn genetic diseases (1)
-	-	1	LOXHD1-related disorder (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.53
CADD	Uncertain	23
DANN	Benign	0.94
DEOGEN2	Benign	0.019	T
Eigen	Pathogenic	0.73
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.93	D
M_CAP	Benign	0.031	D
MetaRNN	Benign	0.032	T
MetaSVM	Benign	-0.81	T
PhyloP100		7.9
PrimateAI	Uncertain	0.58	T
PROVEAN	Uncertain	-2.9	D
REVEL	Uncertain	0.35
Sift	Uncertain	0.028	D
Sift4G	Uncertain	0.0050	D
Polyphen		1.0	D
Vest4		0.57
MVP		0.17
ClinPred		0.10	T
GERP RS		5.7
Varity_R		0.19
gMVP		0.21
Mutation Taster		=41/59	disease causing

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: rs191697915; hg19: chr18-44190776;