NM_015294.6:c.227T>C

Variant names:

• chr17-59088345-A-G
• rs386834004
• NM_015294.6:c.227T>C

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2 PP3_Moderate PP5

The NM_015294.6(TRIM37):​c.227T>C​(p.Leu76Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,618 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: TRIM37 NM_015294.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:1
• Conservation: PhyloP100: 9.23
• Publications: 4 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.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.868
• PP5: Variant 17-59088345-A-G is Pathogenic according to our data. Variant chr17-59088345-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 56569.

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.227T>C	p.Leu76Pro	missense	Exon 4 of 24	NP_056109.1
	TRIM37	NM_001353085.2		c.-148T>C		5_prime_UTR_premature_start_codon_gain	Exon 3 of 22	NP_001340014.1
	TRIM37	NM_001320990.3		c.-140T>C		5_prime_UTR_premature_start_codon_gain	Exon 5 of 24	NP_001307919.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TRIM37	ENST00000262294.12	TSL:1 MANE Select	c.227T>C	p.Leu76Pro	missense	Exon 4 of 24	ENSP00000262294.7
	TRIM37	ENST00000393066.7	TSL:1	c.227T>C	p.Leu76Pro	missense	Exon 4 of 25	ENSP00000376785.3
	TRIM37	ENST00000577554.5	TSL:1	n.*99T>C		non_coding_transcript_exon	Exon 5 of 24	ENSP00000462340.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000798 AC: 2 AN: 250586 AF XY: 0.00000738

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000925

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461618 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 727088

African (AFR) AF: 0.00 AC: 0 AN: 33470

American (AMR) AF: 0.00 AC: 0 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26124

East Asian (EAS) AF: 0.00 AC: 0 AN: 39680

South Asian (SAS) AF: 0.00 AC: 0 AN: 86232

European-Finnish (FIN) AF: 0.0000375 AC: 2 AN: 53398

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111858

Other (OTH) AF: 0.00 AC: 0 AN: 60374

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
2	-	-	Mulibrey nanism syndrome (2)
-	1	-	TRIM37-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.36
CADD	Pathogenic	31
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.61	D
Eigen	Uncertain	0.67
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.95	D
M_CAP	Benign	0.058	D
MetaRNN	Pathogenic	0.87	D
MetaSVM	Benign	-0.70	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		9.2
PrimateAI	Pathogenic	0.93	D
PROVEAN	Pathogenic	-5.3	D
REVEL	Pathogenic	0.68
Sift	Uncertain	0.0040	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.98
MutPred		0.61		Gain of catalytic residue at L76 (P = 0.0353)
MVP		0.95
MPC		2.0
ClinPred		0.98	D
GERP RS		5.4
Varity_R		0.96
gMVP		0.93
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs386834004; hg19: chr17-57165706;