6-35805641-G-C
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Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2BP4_StrongBS1_Supporting
The NM_182548.4(LHFPL5):c.-30G>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00021 in 1,613,132 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: 𝑓 0.00013 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00022 ( 0 hom. )
Consequence
LHFPL5
NM_182548.4 5_prime_UTR
NM_182548.4 5_prime_UTR
Scores
2
Clinical Significance
Conservation
PhyloP100: 0.279
Genes affected
LHFPL5 (HGNC:21253): (LHFPL tetraspan subfamily member 5) This gene is a member of the lipoma HMGIC fusion partner (LHFP) gene family, which is a subset of the superfamily of tetraspan transmembrane protein encoding genes. Mutations in this gene result in deafness in humans, and a mutation in a similar gene in mice results in deafness and vestibular dysfunction with severe degeneration of the organ of Corti. It is proposed to function in hair bundle morphogenesis. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -3 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.76).
BS1
Variant frequency is greater than expected in population nfe. gnomad4_exome allele frequency = 0.000218 (319/1460978) while in subpopulation NFE AF= 0.00028 (311/1111628). AF 95% confidence interval is 0.000254. There are 0 homozygotes in gnomad4_exome. There are 139 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
|---|---|---|---|---|---|---|---|
| LHFPL5 | NM_182548.4 | c.-30G>C | 5_prime_UTR_variant | 1/4 | ENST00000360215.3 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| LHFPL5 | ENST00000360215.3 | c.-30G>C | 5_prime_UTR_variant | 1/4 | 1 | NM_182548.4 | P1 | ||
| LHFPL5 | ENST00000651132.1 | c.-30G>C | 5_prime_UTR_variant | 4/7 | P1 | ||||
| LHFPL5 | ENST00000651676.1 | c.-30G>C | 5_prime_UTR_variant | 1/4 | P1 | ||||
| LHFPL5 | ENST00000651994.1 | c.-30G>C | 5_prime_UTR_variant, NMD_transcript_variant | 1/4 |
Frequencies
GnomAD3 genomes 0.000131 AC: 20AN: 152154Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000997 AC: 25AN: 250748Hom.: 0 AF XY: 0.000103 AC XY: 14AN XY: 135634
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GnomAD4 exome AF: 0.000218 AC: 319AN: 1460978Hom.: 0 Cov.: 31 AF XY: 0.000191 AC XY: 139AN XY: 726826
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GnomAD4 genome 0.000131 AC: 20AN: 152154Hom.: 0 Cov.: 32 AF XY: 0.000121 AC XY: 9AN XY: 74320
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Autosomal recessive nonsyndromic hearing loss 67 Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 12, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. - |
Computational scores
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at