NM_001384474.1:c.4868A>G

Variant names:

• chr18-46524474-T-C
• rs12606417
• NM_001384474.1:c.4868A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001384474.1(LOXHD1):​c.4868A>G​(p.Glu1623Gly) variant causes a missense change. The variant allele was found at a frequency of 0.0916 in 1,551,170 control chromosomes in the GnomAD database, including 7,016 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.071 (516 hom., cov: 33)
  • Exomes 𝑓: 0.094 (6500 hom.)
• Consequence: LOXHD1 NM_001384474.1 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 4.34
• Publications: 21 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0017565191).
• BP6: Variant 18-46524474-T-C is Benign according to our data. Variant chr18-46524474-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 47941.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0983 is higher than 0.05.

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.4868A>G	p.Glu1623Gly	missense	Exon 31 of 41	NP_001371403.1	A0A2R8Y7K4
	LOXHD1	NM_144612.7		c.4868A>G	p.Glu1623Gly	missense	Exon 31 of 40	NP_653213.6
	LOXHD1	NM_001145472.3		c.1535A>G	p.Glu512Gly	missense	Exon 13 of 24	NP_001138944.1	Q8IVV2-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LOXHD1	ENST00000642948.1	MANE Select	c.4868A>G	p.Glu1623Gly	missense	Exon 31 of 41	ENSP00000496347.1	A0A2R8Y7K4
	LOXHD1	ENST00000300591.11	TSL:1	c.1535A>G	p.Glu512Gly	missense	Exon 13 of 24	ENSP00000300591.6	Q8IVV2-3
	LOXHD1	ENST00000579038.6	TSL:1	c.1247A>G	p.Glu416Gly	missense	Exon 11 of 22	ENSP00000463285.1	J3QKX9

Frequencies

GnomAD3 genomes AF: 0.0712 AC: 10835 AN: 152190 Hom.: 516 Cov.: 33

Gnomad AFR AF: 0.0227

Gnomad AMI AF: 0.253

Gnomad AMR AF: 0.0764

Gnomad ASJ AF: 0.0934

Gnomad EAS AF: 0.0594

Gnomad SAS AF: 0.0738

Gnomad FIN AF: 0.0444

Gnomad MID AF: 0.0728

Gnomad NFE AF: 0.100

Gnomad OTH AF: 0.0937

GnomAD2 exomes AF: 0.0767 AC: 12120 AN: 158082 AF XY: 0.0792

Gnomad AFR exome AF: 0.0233

Gnomad AMR exome AF: 0.0530

Gnomad ASJ exome AF: 0.0969

Gnomad EAS exome AF: 0.0615

Gnomad FIN exome AF: 0.0452

Gnomad NFE exome AF: 0.101

Gnomad OTH exome AF: 0.0900

GnomAD4 exome AF: 0.0938 AC: 131206 AN: 1398862 Hom.: 6500 Cov.: 32 AF XY: 0.0938 AC XY: 64676 AN XY: 689818

African (AFR) AF: 0.0183 AC: 577 AN: 31588

American (AMR) AF: 0.0551 AC: 1968 AN: 35694

Ashkenazi Jewish (ASJ) AF: 0.0955 AC: 2405 AN: 25182

East Asian (EAS) AF: 0.0396 AC: 1415 AN: 35722

South Asian (SAS) AF: 0.0800 AC: 6335 AN: 79228

European-Finnish (FIN) AF: 0.0486 AC: 2397 AN: 49272

Middle Eastern (MID) AF: 0.0748 AC: 426 AN: 5696

European-Non Finnish (NFE) AF: 0.102 AC: 110396 AN: 1078516

Other (OTH) AF: 0.0912 AC: 5287 AN: 57964

GnomAD4 genome AF: 0.0711 AC: 10829 AN: 152308 Hom.: 516 Cov.: 33 AF XY: 0.0690 AC XY: 5140 AN XY: 74476

African (AFR) AF: 0.0226 AC: 941 AN: 41570

American (AMR) AF: 0.0763 AC: 1167 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0934 AC: 324 AN: 3470

East Asian (EAS) AF: 0.0588 AC: 305 AN: 5186

South Asian (SAS) AF: 0.0734 AC: 354 AN: 4822

European-Finnish (FIN) AF: 0.0444 AC: 472 AN: 10628

Middle Eastern (MID) AF: 0.0748 AC: 22 AN: 294

European-Non Finnish (NFE) AF: 0.100 AC: 6818 AN: 68012

Other (OTH) AF: 0.0927 AC: 196 AN: 2114

Alfa AF: 0.0910 Hom.: 2937

Bravo AF: 0.0711

TwinsUK AF: 0.103 AC: 381

ALSPAC AF: 0.0986 AC: 380

ESP6500AA AF: 0.0260 AC: 36

ESP6500EA AF: 0.115 AC: 366

ExAC AF: 0.0742 AC: 1881

Asia WGS AF: 0.0590 AC: 204 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.50
CADD	Uncertain	26
DANN	Uncertain	0.98
DEOGEN2	Benign	0.074	T
Eigen	Benign	-0.0081
Eigen_PC	Benign	0.088
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.87	D
MetaRNN	Benign	0.0018	T
MetaSVM	Benign	-1.1	T
PhyloP100		4.3
PrimateAI	Benign	0.38	T
PROVEAN	Uncertain	-3.1	D
REVEL	Benign	0.069
Sift	Benign	0.055	T
Sift4G	Uncertain	0.057	T
Polyphen		0.97	D
Vest4		0.19
ClinPred		0.034	T
GERP RS		5.1
Varity_R		0.65
gMVP		0.45
Mutation Taster		=86/14	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: rs12606417; hg19: chr18-44104437; COSMIC: COSV56061462; COSMIC: COSV56061462;