chr6-35805671-A-G
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate
The NM_182548.4(LHFPL5):c.1A>G(p.Met1?) variant causes a start lost change. The variant allele was found at a frequency of 0.000000684 in 1,461,852 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 6.8e-7 ( 0 hom. )
Consequence
LHFPL5
NM_182548.4 start_lost
NM_182548.4 start_lost
Scores
6
4
5
Clinical Significance
Conservation
PhyloP100: 6.15
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]
Genome browser will be placed here
ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 12 ACMG points.
PVS1
?
Start lost variant, no new inframe start found.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 6-35805671-A-G is Pathogenic according to our data. Variant chr6-35805671-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 402282.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr6-35805671-A-G is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
LHFPL5 | NM_182548.4 | c.1A>G | p.Met1? | start_lost | 1/4 | ENST00000360215.3 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
LHFPL5 | ENST00000360215.3 | c.1A>G | p.Met1? | start_lost | 1/4 | 1 | NM_182548.4 | P1 | |
LHFPL5 | ENST00000651132.1 | c.1A>G | p.Met1? | start_lost | 4/7 | P1 | |||
LHFPL5 | ENST00000651676.1 | c.1A>G | p.Met1? | start_lost | 1/4 | P1 | |||
LHFPL5 | ENST00000651994.1 | c.1A>G | p.Met1? | start_lost, NMD_transcript_variant | 1/4 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461852Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 727230
GnomAD4 exome
AF:
AC:
1
AN:
1461852
Hom.:
Cov.:
31
AF XY:
AC XY:
0
AN XY:
727230
Gnomad4 AFR exome
AF:
Gnomad4 AMR exome
AF:
Gnomad4 ASJ exome
AF:
Gnomad4 EAS exome
AF:
Gnomad4 SAS exome
AF:
Gnomad4 FIN exome
AF:
Gnomad4 NFE exome
AF:
Gnomad4 OTH exome
AF:
GnomAD4 genome ? Cov.: 32
GnomAD4 genome
?
Cov.:
32
Bravo
AF:
ClinVar
Significance: Likely pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Autosomal recessive nonsyndromic hearing loss 67 Pathogenic:2
Likely pathogenic, criteria provided, single submitter | research | King Laboratory, University of Washington | Aug 01, 2020 | LHFPL5 c.1A>G, p.M1V alters the first codon of LHFPL5, leading to loss of the translation start. The entire N-terminal cytoplasmic domain of the protein lises between codon 1 and the next Met at codon 28. The variant is homozygous in 5 Palestinian children with pre-lingual severe to profound hearing loss (Abu Rayyan 2020). It is absent from 1300 Palestinian controls and absent from gnomAD v2.1.1. - |
Pathogenic, no assertion criteria provided | research | Hereditary Research Laboratory, Bethlehem University | Jun 04, 2016 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
Cadd
Benign
Dann
Uncertain
DEOGEN2
Benign
T;T
Eigen
Benign
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D
MetaSVM
Benign
T
MutationTaster
Benign
D;D
PROVEAN
Benign
N;.
REVEL
Uncertain
Sift
Pathogenic
D;.
Sift4G
Pathogenic
D;.
Polyphen
B;B
Vest4
MutPred
Loss of catalytic residue at M1 (P = 0.0395);Loss of catalytic residue at M1 (P = 0.0395);
MVP
ClinPred
D
GERP RS
Varity_R
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at