rs16978578

Variant names:

• chr18-46572106-T-C
• rs16978578
• NM_001384474.1:c.2027A>G

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.2027A>G​(p.Asp676Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00135 in 1,551,826 control chromosomes in the GnomAD database, including 30 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. D676D) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0070 (12 hom., cov: 31)
  • Exomes 𝑓: 0.00073 (18 hom.)
• Consequence: LOXHD1 NM_001384474.1 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4
• Conservation: PhyloP100: 0.967
• Publications: 4 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: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0026506186).
• BP6: Variant 18-46572106-T-C is Benign according to our data. Variant chr18-46572106-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 226712.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00704 (1073/152334) while in subpopulation AFR AF = 0.0246 (1022/41578). AF 95% confidence interval is 0.0233. There are 12 homozygotes in GnomAd4. There are 505 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 12 AD,AR 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LOXHD1	NM_001384474.1	MANE Select	c.2027A>G	p.Asp676Gly	missense	Exon 15 of 41	NP_001371403.1
	LOXHD1	NM_144612.7		c.2027A>G	p.Asp676Gly	missense	Exon 15 of 40	NP_653213.6

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LOXHD1	ENST00000642948.1	MANE Select	c.2027A>G	p.Asp676Gly	missense	Exon 15 of 41	ENSP00000496347.1
	LOXHD1	ENST00000536736.5	TSL:5	c.2027A>G	p.Asp676Gly	missense	Exon 15 of 40	ENSP00000444586.1
	LOXHD1	ENST00000441551.6	TSL:5	c.2027A>G	p.Asp676Gly	missense	Exon 15 of 39	ENSP00000387621.2

Frequencies

GnomAD3 genomes AF: 0.00704 AC: 1071 AN: 152216 Hom.: 12 Cov.: 31

Gnomad AFR AF: 0.0246

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00249

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.00152 AC: 241 AN: 158922 AF XY: 0.00114

Gnomad AFR exome AF: 0.0249

Gnomad AMR exome AF: 0.000687

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000326

Gnomad OTH exome AF: 0.000445

GnomAD4 exome AF: 0.000734 AC: 1027 AN: 1399492 Hom.: 18 Cov.: 31 AF XY: 0.000666 AC XY: 460 AN XY: 690246

African (AFR) AF: 0.0279 AC: 881 AN: 31598

American (AMR) AF: 0.000840 AC: 30 AN: 35704

Ashkenazi Jewish (ASJ) AF: 0.0000397 AC: 1 AN: 25182

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

South Asian (SAS) AF: 0.0000631 AC: 5 AN: 79236

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49316

Middle Eastern (MID) AF: 0.000526 AC: 3 AN: 5700

European-Non Finnish (NFE) AF: 0.00000834 AC: 9 AN: 1078992

Other (OTH) AF: 0.00169 AC: 98 AN: 58026

GnomAD4 genome AF: 0.00704 AC: 1073 AN: 152334 Hom.: 12 Cov.: 31 AF XY: 0.00678 AC XY: 505 AN XY: 74504

African (AFR) AF: 0.0246 AC: 1022 AN: 41578

American (AMR) AF: 0.00248 AC: 38 AN: 15298

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.000103 AC: 7 AN: 68030

Other (OTH) AF: 0.00237 AC: 5 AN: 2112

Alfa AF: 0.00322 Hom.: 12

Bravo AF: 0.00828

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.0260 AC: 36

ESP6500EA AF: 0.000314 AC: 1

ExAC AF: 0.00272 AC: 74

Asia WGS AF: 0.00144 AC: 6 AN: 3478

ClinVar

ClinVar submissions as Germline

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 provided (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.75	T
BayesDel_noAF	Benign	-0.83
CADD	Benign	12
DANN	Benign	0.93
Eigen	Benign	-0.38
Eigen_PC	Benign	-0.29
FATHMM_MKL	Benign	0.34	N
LIST_S2	Benign	0.60	T
MetaRNN	Benign	0.0027	T
MetaSVM	Benign	-1.1	T
PhyloP100		0.97
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-0.080	N
REVEL	Benign	0.022
Sift	Benign	0.62	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.13
MVP		0.061
ClinPred		0.0044	T
GERP RS		1.8
Varity_R		0.066
gMVP		0.42
Mutation Taster		=92/8	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs16978578; hg19: chr18-44152069;