chr17-59064406-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_001353084.2(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_001353084.2 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 0.017453799 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 Pathogenic/Likely_pathogenic. ClinVar VariationId is 56571.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001353084.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TRIM37	NM_015294.6	MANE Select	c.810-1G>A		splice_acceptor intron	N/A	NP_056109.1
	TRIM37	NM_001353084.2		c.810-1G>A		splice_acceptor intron	N/A	NP_001340013.1
	TRIM37	NM_001005207.5		c.810-1G>A		splice_acceptor intron	N/A	NP_001005207.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TRIM37	ENST00000262294.12	TSL:1 MANE Select	c.810-1G>A		splice_acceptor intron	N/A	ENSP00000262294.7
	TRIM37	ENST00000393066.7	TSL:1	c.810-1G>A		splice_acceptor intron	N/A	ENSP00000376785.3
	TRIM37	ENST00000577554.5	TSL:1	n.*682-1G>A		splice_acceptor intron	N/A	ENSP00000462340.1

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), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic/Likely pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
2	-	-	Mulibrey nanism syndrome (2)

Computational scores

Source: dbNSFP v4.9

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;