rs727504587

Variant names:

• chr18-46477200-C-A
• rs727504587
• ENST00000300591.11:c.3328G>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001145472.3(LOXHD1):​c.3328G>T​(p.Ala1110Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000175 in 570,004 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000018 (0 hom.)
• Consequence: LOXHD1 NM_001145472.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.571
• 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.070946366).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001145472.3. 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_001145472.3		c.3328G>T	p.Ala1110Ser	missense	Exon 24 of 24	NP_001138944.1
	LOXHD1	NM_001308013.2		c.*18G>T		3_prime_UTR	Exon 22 of 22	NP_001294942.1
	LOXHD1	NM_001173129.2		c.*18G>T		3_prime_UTR	Exon 10 of 10	NP_001166600.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LOXHD1	ENST00000300591.11	TSL:1	c.3328G>T	p.Ala1110Ser	missense	Exon 24 of 24	ENSP00000300591.6
	LOXHD1	ENST00000579038.6	TSL:1	c.*18G>T		3_prime_UTR	Exon 22 of 22	ENSP00000463285.1
	LOXHD1	ENST00000398705.7	TSL:2	c.*18G>T		3_prime_UTR	Exon 10 of 10	ENSP00000381692.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000639 AC: 1 AN: 156542 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000917

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000175 AC: 1 AN: 570004 Hom.: 0 Cov.: 4 AF XY: 0.00 AC XY: 0 AN XY: 307350

African (AFR) AF: 0.00 AC: 0 AN: 15860

American (AMR) AF: 0.00 AC: 0 AN: 34726

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 20068

East Asian (EAS) AF: 0.0000311 AC: 1 AN: 32130

South Asian (SAS) AF: 0.00 AC: 0 AN: 62852

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48990

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4080

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 320458

Other (OTH) AF: 0.00 AC: 0 AN: 30840

GnomAD4 genome Cov.: 33

ExAC AF: 0.0000409 AC: 1

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	14
DANN	Benign	0.97
Eigen	Benign	-0.48
Eigen_PC	Benign	-0.59
FATHMM_MKL	Benign	0.055	N
LIST_S2	Benign	0.40	T
M_CAP	Benign	0.027	D
MetaRNN	Benign	0.071	T
MetaSVM	Benign	-1.0	T
PhyloP100		0.57
PROVEAN	Benign	0.090	N
REVEL	Benign	0.024
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.26	T
Vest4		0.38
MutPred		0.25		Loss of helix (P = 0.0444)
MVP		0.030
ClinPred		0.60	D
GERP RS		3.1
Mutation Taster		=99/1	polymorphism

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs727504587; hg19: chr18-44057163;