chr5-131180095-GT-G
Variant summary
Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PVS1_StrongPM2PP5_Moderate
The NM_181705.4(LYRM7):c.23del(p.Leu8TyrfsTer22) variant causes a frameshift, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,106 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic (★).
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 30)
Exomes 𝑓: 0.0 ( 0 hom. )
Failed GnomAD Quality Control
Consequence
LYRM7
NM_181705.4 frameshift, splice_region
NM_181705.4 frameshift, splice_region
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 2.78
Genes affected
LYRM7 (HGNC:28072): (LYR motif containing 7) Inner mitochondrial membrane complex III (CIII) is the main enzyme complex in the mitochondrial respiratory chain, and Rieske Fe-S protein (UQCRFS1) is the last catalytic subunit added to the complex. The protein encoded by this gene is a nuclear-encoded mitochondrial matrix protein that stabilizes UQCRFS1 and chaperones it to the CIII complex. Defects in this gene are a cause of mitochondrial complex III deficiency, nuclear type 8. Three transcript variants encoding two different isoforms have been found for this gene. [provided by RefSeq, Jun 2014]
HINT1 (HGNC:4912): (histidine triad nucleotide binding protein 1) This gene encodes a protein that hydrolyzes purine nucleotide phosphoramidates substrates, including AMP-morpholidate, AMP-N-alanine methyl ester, AMP-alpha-acetyl lysine methyl ester, and AMP-NH2. The encoded protein interacts with these substrates via a histidine triad motif. This gene is considered a tumor suppressor gene. In addition, mutations in this gene can cause autosomal recessive neuromyotonia and axonal neuropathy. There are several related pseudogenes on chromosome 7. Several transcript variants have been observed. [provided by RefSeq, Dec 2015]
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ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 8 ACMG points.
PVS1
?
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 5 pathogenic variants in the truncated region.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 5-131180095-GT-G is Pathogenic according to our data. Variant chr5-131180095-GT-G is described in ClinVar as [Pathogenic]. Clinvar id is 1907936.Status of the report is criteria_provided_single_submitter, 1 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
LYRM7 | NM_181705.4 | c.23del | p.Leu8TyrfsTer22 | frameshift_variant, splice_region_variant | 2/5 | ENST00000379380.9 | |
LYRM7 | NM_001293735.2 | c.23del | p.Leu8TyrfsTer22 | frameshift_variant, splice_region_variant | 2/4 | ||
LYRM7 | NR_121658.2 | n.100del | splice_region_variant, non_coding_transcript_exon_variant | 2/3 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
LYRM7 | ENST00000379380.9 | c.23del | p.Leu8TyrfsTer22 | frameshift_variant, splice_region_variant | 2/5 | 1 | NM_181705.4 | P1 | |
LYRM7 | ENST00000507584.1 | c.23del | p.Leu8TyrfsTer22 | frameshift_variant, splice_region_variant | 2/4 | 2 | |||
LYRM7 | ENST00000510516.5 | c.23del | p.Leu8TyrfsTer22 | frameshift_variant, splice_region_variant | 2/3 | 2 | |||
HINT1 | ENST00000506207.2 | n.109-8363del | intron_variant, non_coding_transcript_variant | 5 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152106Hom.: 0 Cov.: 30
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GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0AN: 1456718Hom.: 0 Cov.: 28 AF XY: 0.00 AC XY: 0AN XY: 725016
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Sep 09, 2022 | For these reasons, this variant has been classified as Pathogenic. This variant has not been reported in the literature in individuals affected with LYRM7-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Leu8Tyrfs*22) in the LYRM7 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in LYRM7 are known to be pathogenic (PMID: 26912632). - |
Computational scores
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Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at