17-59064406-C-T

Variant names:

• chr17-59064406-C-T
• rs386834006
• NM_015294.6:c.810-1G>A

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PVS1_Moderate PM2 PP5

The NM_015294.6(TRIM37):​c.810-1G>A variant causes a splice acceptor, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000709 in 1,409,624 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: TRIM37 NM_015294.6 splice_acceptor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic/Likely pathogenic no assertion criteria provided P:2
• Conservation: PhyloP100: 7.26
• Publications: 1 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: Orphanet, Labcorp Genetics (formerly Invitae), ClinGen, Ambry Genetics, G2P

ACMG classification

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.017616581 fraction of the gene. Cryptic splice site detected, with MaxEntScore 5, offset of 8, new splice context is: ttttttttttaatgaattAGtgc. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 17-59064406-C-T is Pathogenic according to our data. Variant chr17-59064406-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 56571.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TRIM37	NM_015294.6	c.810-1G>A		splice_acceptor_variant, intron_variant	Intron 9 of 23	ENST00000262294.12	NP_056109.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TRIM37	ENST00000262294.12	c.810-1G>A		splice_acceptor_variant, intron_variant	Intron 9 of 23	1	NM_015294.6	ENSP00000262294.7

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.09e-7 AC: 1 AN: 1409624 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 700186

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000322 AC: 1 AN: 31102

American (AMR) AF: 0.00 AC: 0 AN: 37960

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24872

East Asian (EAS) AF: 0.00 AC: 0 AN: 39008

South Asian (SAS) AF: 0.00 AC: 0 AN: 78736

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52028

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4838

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1083038

Other (OTH) AF: 0.00 AC: 0 AN: 58042

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2

Revision: no assertion criteria provided

Submissions by phenotype

Mulibrey nanism syndrome Pathogenic:2

Jun 01, 2003

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

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Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM)

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.42
CADD	Pathogenic	34
DANN	Uncertain	0.99
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.98
FATHMM_MKL	Pathogenic	0.99	D
PhyloP100		7.3
GERP RS		5.0
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.94
SpliceAI score (max)		0.98		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.34		Position offset: -9
DS_AL_spliceai		0.98		Position offset: -1

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

Other links and lift over

dbSNP: rs386834006; hg19: chr17-57141767;