rs74316327

Variant names:

• chr18-46477710-C-T
• rs74316327
• NM_001384474.1:c.6584G>A

Your query was ambiguous. Multiple possible variants found:

• chr18-46477710-C-T
• chr18-46477710-C-A

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.6584G>A​(p.Arg2195His) variant causes a missense change. The variant allele was found at a frequency of 0.0625 in 1,551,918 control chromosomes in the GnomAD database, including 3,482 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. R2195R) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.047 (257 hom., cov: 33)
  • Exomes 𝑓: 0.064 (3225 hom.)
• Consequence: LOXHD1 NM_001384474.1 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 5.02
• Publications: 15 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=0.0019818544).
• BP6: Variant 18-46477710-C-T is Benign according to our data. Variant chr18-46477710-C-T is described in ClinVar as Benign. ClinVar VariationId is 47951.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0693 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.6584G>A	p.Arg2195His	missense	Exon 41 of 41	NP_001371403.1	A0A2R8Y7K4
	LOXHD1	NM_144612.7		c.6398G>A	p.Arg2133His	missense	Exon 40 of 40	NP_653213.6
	LOXHD1	NM_001145472.3		c.3251G>A	p.Arg1084His	missense	Exon 23 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.6584G>A	p.Arg2195His	missense	Exon 41 of 41	ENSP00000496347.1	A0A2R8Y7K4
	LOXHD1	ENST00000300591.11	TSL:1	c.3251G>A	p.Arg1084His	missense	Exon 23 of 24	ENSP00000300591.6	Q8IVV2-3
	LOXHD1	ENST00000579038.6	TSL:1	c.2963G>A	p.Arg988His	missense	Exon 21 of 22	ENSP00000463285.1	J3QKX9

Frequencies

GnomAD3 genomes AF: 0.0474 AC: 7212 AN: 152238 Hom.: 257 Cov.: 33

Gnomad AFR AF: 0.0137

Gnomad AMI AF: 0.182

Gnomad AMR AF: 0.0599

Gnomad ASJ AF: 0.0603

Gnomad EAS AF: 0.000963

Gnomad SAS AF: 0.0267

Gnomad FIN AF: 0.0227

Gnomad MID AF: 0.0380

Gnomad NFE AF: 0.0709

Gnomad OTH AF: 0.0664

GnomAD2 exomes AF: 0.0482 AC: 7575 AN: 157258 AF XY: 0.0483

Gnomad AFR exome AF: 0.0132

Gnomad AMR exome AF: 0.0447

Gnomad ASJ exome AF: 0.0675

Gnomad EAS exome AF: 0.00101

Gnomad FIN exome AF: 0.0233

Gnomad NFE exome AF: 0.0719

Gnomad OTH exome AF: 0.0669

GnomAD4 exome AF: 0.0641 AC: 89728 AN: 1399562 Hom.: 3225 Cov.: 31 AF XY: 0.0636 AC XY: 43869 AN XY: 690282

African (AFR) AF: 0.0102 AC: 321 AN: 31598

American (AMR) AF: 0.0451 AC: 1609 AN: 35704

Ashkenazi Jewish (ASJ) AF: 0.0672 AC: 1693 AN: 25182

East Asian (EAS) AF: 0.000728 AC: 26 AN: 35738

South Asian (SAS) AF: 0.0332 AC: 2632 AN: 79236

European-Finnish (FIN) AF: 0.0239 AC: 1179 AN: 49342

Middle Eastern (MID) AF: 0.0542 AC: 309 AN: 5698

European-Non Finnish (NFE) AF: 0.0727 AC: 78438 AN: 1079018

Other (OTH) AF: 0.0607 AC: 3521 AN: 58046

GnomAD4 genome AF: 0.0474 AC: 7217 AN: 152356 Hom.: 257 Cov.: 33 AF XY: 0.0449 AC XY: 3342 AN XY: 74508

African (AFR) AF: 0.0137 AC: 568 AN: 41596

American (AMR) AF: 0.0599 AC: 916 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0603 AC: 209 AN: 3464

East Asian (EAS) AF: 0.000965 AC: 5 AN: 5182

South Asian (SAS) AF: 0.0275 AC: 133 AN: 4830

European-Finnish (FIN) AF: 0.0227 AC: 241 AN: 10624

Middle Eastern (MID) AF: 0.0408 AC: 12 AN: 294

European-Non Finnish (NFE) AF: 0.0710 AC: 4828 AN: 68040

Other (OTH) AF: 0.0658 AC: 139 AN: 2114

Alfa AF: 0.0617 Hom.: 725

Bravo AF: 0.0483

TwinsUK AF: 0.0731 AC: 271

ALSPAC AF: 0.0688 AC: 265

ESP6500AA AF: 0.0145 AC: 20

ESP6500EA AF: 0.0798 AC: 254

ExAC AF: 0.0426 AC: 1120

Asia WGS AF: 0.0180 AC: 61 AN: 3478

ClinVar

ClinVar submissions

Significance: 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	0.10
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.41
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.049	T
Eigen	Benign	0.050
Eigen_PC	Benign	0.20
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.80	T
MetaRNN	Benign	0.0020	T
MetaSVM	Benign	-1.1	T
PhyloP100		5.0
PrimateAI	Benign	0.39	T
PROVEAN	Uncertain	-3.4	D
REVEL	Benign	0.029
Sift	Benign	0.17	T
Sift4G	Benign	0.13	T
Polyphen		0.0040	B
Vest4		0.18
ClinPred		0.030	T
GERP RS		4.3
Varity_R		0.13
gMVP		0.30
Mutation Taster		=81/19	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: rs74316327; hg19: chr18-44057673; COSMIC: COSV56060930;