17-59088344-AA-CG

Variant names:

• chr17-59088344-AA-CG
• NM_015294.6:c.227_228delTTinsCG
• TRIM37 p.Leu76Pro

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PS1_Moderate PP3

The NM_015294.6(TRIM37):​c.227_228delTTinsCG​(p.Leu76Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type MNV, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely pathogenic in ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TRIM37 NM_015294.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.23
• Publications: 0 publications found

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]

TRIM37 Gene-Disease associations (from GenCC):

• mulibrey nanism

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Orphanet, ClinGen, Ambry Genetics, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PS1: Transcript NM_015294.6 (TRIM37) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar.
• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015294.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TRIM37	NM_015294.6	MANE Select	c.227_228delTTinsCG	p.Leu76Pro	missense	N/A	NP_056109.1	O94972-1
	TRIM37	NM_001353084.2		c.227_228delTTinsCG	p.Leu76Pro	missense	N/A	NP_001340013.1
	TRIM37	NM_001005207.5		c.227_228delTTinsCG	p.Leu76Pro	missense	N/A	NP_001005207.1	O94972-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TRIM37	ENST00000262294.12	TSL:1 MANE Select	c.227_228delTTinsCG	p.Leu76Pro	missense	N/A	ENSP00000262294.7	O94972-1
	TRIM37	ENST00000393066.7	TSL:1	c.227_228delTTinsCG	p.Leu76Pro	missense	N/A	ENSP00000376785.3	O94972-1
	TRIM37	ENST00000577554.5	TSL:1	n.*99_*100delTTinsCG		non_coding_transcript_exon	Exon 5 of 24	ENSP00000462340.1	J3KS72

Frequencies

GnomAD3 genomes Cov.: 32

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

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		9.2

Splicing

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr17-57165705;