NM_001384474.1:c.1759C>A

Variant names:

• chr18-46579680-G-T
• rs540100675
• NM_001384474.1:c.1759C>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Moderate BP6_Moderate

The NM_001384474.1(LOXHD1):​c.1759C>A​(p.Arg587Arg) variant causes a synonymous change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: LOXHD1 NM_001384474.1 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 5.03
• 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (REVEL=0.113).
• BP6: Variant 18-46579680-G-T is Benign according to our data. Variant chr18-46579680-G-T is described in CliVar as Likely_benign. Clinvar id is 1147706.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr18-46579680-G-T is described in CliVar as Likely_benign. Clinvar id is 1147706.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr18-46579680-G-T is described in CliVar as Likely_benign. Clinvar id is 1147706.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr18-46579680-G-T is described in CliVar as Likely_benign. Clinvar id is 1147706.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr18-46579680-G-T is described in CliVar as Likely_benign. Clinvar id is 1147706.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LOXHD1	NM_001384474.1	c.1759C>A	p.Arg587Arg	synonymous_variant	Exon 13 of 41	ENST00000642948.1	NP_001371403.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LOXHD1	ENST00000642948.1	c.1759C>A	p.Arg587Arg	synonymous_variant	Exon 13 of 41		NM_001384474.1	ENSP00000496347.1
LOXHD1	ENST00000536736.5	c.1759C>A	p.Arg587Arg	synonymous_variant	Exon 13 of 40	5		ENSP00000444586.1
LOXHD1	ENST00000441551.6	c.1759C>A	p.Arg587Arg	synonymous_variant	Exon 13 of 39	5		ENSP00000387621.2
LOXHD1	ENST00000335730.6	n.1072C>A		non_coding_transcript_exon_variant	Exon 6 of 27	2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Dec 13, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.31
CADD	Benign	11
DANN	Benign	0.70
PhyloP100		5.0

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: rs540100675; hg19: chr18-44159643;