rs876657857

Variant names:

• chr18-46649279-GA-TT
• rs876657857
• NM_001384474.1:c.131-11_131-10delTCinsAA

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001384474.1(LOXHD1):​c.131-11_131-10delTCinsAA variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: LOXHD1 NM_001384474.1 intron
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 2.72

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LOXHD1	NM_001384474.1	c.131-11_131-10delTCinsAA		intron_variant	Intron 1 of 40	ENST00000642948.1	NP_001371403.1
LOXHD1	NM_144612.7	c.131-11_131-10delTCinsAA		intron_variant	Intron 1 of 39		NP_653213.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LOXHD1	ENST00000642948.1	c.131-11_131-10delTCinsAA		intron_variant	Intron 1 of 40		NM_001384474.1	ENSP00000496347.1
LOXHD1	ENST00000536736.5	c.131-11_131-10delTCinsAA		intron_variant	Intron 1 of 39	5		ENSP00000444586.1
LOXHD1	ENST00000441551.6	c.131-11_131-10delTCinsAA		intron_variant	Intron 1 of 38	5		ENSP00000387621.2

Frequencies

GnomAD3 genomes Cov.: 33

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

May 28, 2015

The c.131-11_131-10delinsAA variant in LOXHD1 has not been previously reported i n individuals with hearing loss. Data from large population studies are insuffic ient to assess the frequency of this variant. This variant is located in the 3' splice region. Computational tools do not suggest an impact to splicing. However , this information is not predictive enough to rule out pathogenicity. In summar y, the clinical significance of the c.131-11_131-10delinsAA variant is uncertain . -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 22, 2024

This sequence change falls in intron 1 of the LOXHD1 gene. It does not directly change the encoded amino acid sequence of the LOXHD1 protein. Information on the frequency of this variant in the gnomAD database is not available, as this variant may be reported differently in the database. This variant has not been reported in the literature in individuals affected with LOXHD1-related conditions. ClinVar contains an entry for this variant (Variation ID: 228812). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs876657857; hg19: chr18-44229242;