NM_001384474.1:c.1617G>A

Variant names:

• chr18-46591970-C-T
• rs143142227
• NM_001384474.1:c.1617G>A

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.1617G>A​(p.Met539Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000277 in 1,552,012 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0016 (2 hom., cov: 32)
  • Exomes 𝑓: 0.00014 (0 hom.)
• Consequence: LOXHD1 NM_001384474.1 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:5
• Conservation: PhyloP100: 0.956
• Publications: 2 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.007528752).
• BP6: Variant 18-46591970-C-T is Benign according to our data. Variant chr18-46591970-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 163929.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00158 (240/152328) while in subpopulation AFR AF = 0.00548 (228/41568). AF 95% confidence interval is 0.0049. There are 2 homozygotes in GnomAd4. There are 110 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 AR,AD 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.1617G>A	p.Met539Ile	missense	Exon 12 of 41	NP_001371403.1	A0A2R8Y7K4
	LOXHD1	NM_144612.7		c.1617G>A	p.Met539Ile	missense	Exon 12 of 40	NP_653213.6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LOXHD1	ENST00000642948.1	MANE Select	c.1617G>A	p.Met539Ile	missense	Exon 12 of 41	ENSP00000496347.1	A0A2R8Y7K4
	LOXHD1	ENST00000536736.5	TSL:5	c.1617G>A	p.Met539Ile	missense	Exon 12 of 40	ENSP00000444586.1	F5GZB4
	LOXHD1	ENST00000441551.6	TSL:5	c.1617G>A	p.Met539Ile	missense	Exon 12 of 39	ENSP00000387621.2	Q8IVV2-1

Frequencies

GnomAD3 genomes AF: 0.00158 AC: 240 AN: 152210 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.00550

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000720

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000300 AC: 48 AN: 160000 AF XY: 0.000167

Gnomad AFR exome AF: 0.00477

Gnomad AMR exome AF: 0.000161

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000220

GnomAD4 exome AF: 0.000136 AC: 190 AN: 1399684 Hom.: 0 Cov.: 32 AF XY: 0.000119 AC XY: 82 AN XY: 690338

African (AFR) AF: 0.00513 AC: 162 AN: 31596

American (AMR) AF: 0.000112 AC: 4 AN: 35706

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25180

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 79234

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49414

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5698

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1079018

Other (OTH) AF: 0.000413 AC: 24 AN: 58100

GnomAD4 genome AF: 0.00158 AC: 240 AN: 152328 Hom.: 2 Cov.: 32 AF XY: 0.00148 AC XY: 110 AN XY: 74494

African (AFR) AF: 0.00548 AC: 228 AN: 41568

American (AMR) AF: 0.000719 AC: 11 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

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: 0.00 AC: 0 AN: 68040

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

Alfa AF: 0.000488 Hom.: 0

Bravo AF: 0.00195

ESP6500AA AF: 0.00867 AC: 12

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000818 AC: 22

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.77
BayesDel_addAF	Benign	-0.63	T
BayesDel_noAF	Benign	-0.68
CADD	Benign	19
DANN	Uncertain	0.98
Eigen	Benign	-0.50
Eigen_PC	Benign	-0.23
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Benign	0.85	T
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.0075	T
MetaSVM	Benign	-0.90	T
PhyloP100		0.96
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-0.57	N
REVEL	Benign	0.055
Sift	Benign	0.23	T
Sift4G	Benign	0.30	T
Polyphen		0.0030	B
Vest4		0.21
MutPred		0.52		Loss of catalytic residue at M539 (P = 0.0601)
MVP		0.030
ClinPred		0.021	T
GERP RS		3.1
Varity_R		0.25
gMVP		0.40
Mutation Taster		=84/16	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: rs143142227; hg19: chr18-44171933;