rs386834002
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Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_015294.6(TRIM37):βc.1894_1895delβ(p.Glu632LysfsTer25) variant causes a frameshift change. The variant allele was found at a frequency of 0.00000496 in 1,613,994 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (β β ). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: π 0.000013 ( 0 hom., cov: 32)
Exomes π: 0.0000041 ( 0 hom. )
Consequence
TRIM37
NM_015294.6 frameshift
NM_015294.6 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 6.60
Genes affected
TRIM37 (HGNC:7523): (tripartite motif containing 37) This gene encodes a member of the tripartite motif (TRIM) family, whose members are involved in diverse cellular functions such as developmental patterning and oncogenesis. The TRIM motif includes zinc-binding domains, a RING finger region, a B-box motif and a coiled-coil domain. The RING finger and B-box domains chelate zinc and might be involved in protein-protein and/or protein-nucleic acid interactions. Mutations in this gene are associated with mulibrey (muscle-liver-brain-eye) nanism, an autosomal recessive disorder that involves several tissues of mesodermal origin. TRIM37 localizes in peroxisomal membranes, and has been implicated in human peroxisomal biogenesis disorders. [provided by RefSeq, Jul 2020]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 18 ACMG points.
PVS1
?
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 17-59031948-TTC-T is Pathogenic according to our data. Variant chr17-59031948-TTC-T is described in ClinVar as [Pathogenic]. Clinvar id is 56566.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-59031948-TTC-T is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TRIM37 | NM_015294.6 | c.1894_1895del | p.Glu632LysfsTer25 | frameshift_variant | 18/24 | ENST00000262294.12 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TRIM37 | ENST00000262294.12 | c.1894_1895del | p.Glu632LysfsTer25 | frameshift_variant | 18/24 | 1 | NM_015294.6 | P1 | |
TRIM37 | ENST00000393066.7 | c.1894_1895del | p.Glu632LysfsTer25 | frameshift_variant | 18/25 | 1 | P1 | ||
TRIM37 | ENST00000577554.5 | c.*1766_*1767del | 3_prime_UTR_variant, NMD_transcript_variant | 19/24 | 1 | ||||
TRIM37 | ENST00000393065.6 | c.1792_1793del | p.Glu598LysfsTer25 | frameshift_variant | 17/23 | 2 |
Frequencies
GnomAD3 genomes ? AF: 0.0000131 AC: 2AN: 152172Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251398Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135876
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GnomAD4 exome AF: 0.00000410 AC: 6AN: 1461822Hom.: 0 AF XY: 0.00000550 AC XY: 4AN XY: 727218
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GnomAD4 genome ? AF: 0.0000131 AC: 2AN: 152172Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74346
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Mulibrey nanism syndrome Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Oct 24, 2022 | - - |
Likely pathogenic, no assertion criteria provided | literature only | Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM) | - | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Mar 08, 2023 | For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 56566). This premature translational stop signal has been observed in individual(s) with mulibrey nanism (PMID: 17551331). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change creates a premature translational stop signal (p.Glu632Lysfs*25) in the TRIM37 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in TRIM37 are known to be pathogenic (PMID: 10888877, 15108285). - |
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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