rs61758100

chr17-59081191-G-Achr17-59081191-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_015294.6(TRIM37):c.398C>T(p.Ala133Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00808 in 1,613,754 control chromosomes in the GnomAD database, including 73 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A133G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0064 (4 hom., cov: 32)
  • Exomes 𝑓: 0.0083 (69 hom.)
• Consequence: TRIM37 NM_015294.6 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 7.67

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008718789).
• BP6: Variant 17-59081191-G-A is Benign according to our data. Variant chr17-59081191-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 198216.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-59081191-G-A is described in Lovd as [Likely_benign]. Variant chr17-59081191-G-A is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0064 (974/152202) while in subpopulation NFE AF= 0.011 (750/68020). AF 95% confidence interval is 0.0104. There are 4 homozygotes in gnomad4. There are 497 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TRIM37	NM_015294.6	c.398C>T	p.Ala133Val	missense_variant	6/24	ENST00000262294.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TRIM37	ENST00000262294.12	c.398C>T	p.Ala133Val	missense_variant	6/24	1	NM_015294.6	P1

Frequencies

GnomAD3 genomes AF: 0.00640 AC: 974 AN: 152084 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.00130

Gnomad AMI AF: 0.0132

Gnomad AMR AF: 0.00203

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.000622

Gnomad FIN AF: 0.0104

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0110

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.00630 AC: 1583 AN: 251448 Hom.: 12 AF XY: 0.00630 AC XY: 856 AN XY: 135892

Gnomad AFR exome AF: 0.00135

Gnomad AMR exome AF: 0.00182

Gnomad ASJ exome AF: 0.000794

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000751

Gnomad FIN exome AF: 0.0129

Gnomad NFE exome AF: 0.0101

Gnomad OTH exome AF: 0.00717

GnomAD4 exome AF: 0.00825 AC: 12061 AN: 1461552 Hom.: 69 Cov.: 30 AF XY: 0.00806 AC XY: 5860 AN XY: 727096

Gnomad4 AFR exome AF: 0.000896

Gnomad4 AMR exome AF: 0.00161

Gnomad4 ASJ exome AF: 0.00142

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000939

Gnomad4 FIN exome AF: 0.0130

Gnomad4 NFE exome AF: 0.00972

Gnomad4 OTH exome AF: 0.00553

GnomAD4 genome AF: 0.00640 AC: 974 AN: 152202 Hom.: 4 Cov.: 32 AF XY: 0.00668 AC XY: 497 AN XY: 74404

Gnomad4 AFR AF: 0.00130

Gnomad4 AMR AF: 0.00203

Gnomad4 ASJ AF: 0.00202

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.000623

Gnomad4 FIN AF: 0.0104

Gnomad4 NFE AF: 0.0110

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.00860 Hom.: 6

Bravo AF: 0.00519

TwinsUK AF: 0.00701 AC: 26

ALSPAC AF: 0.00830 AC: 32

ESP6500AA AF: 0.00250 AC: 11

ESP6500EA AF: 0.00919 AC: 79

ExAC AF: 0.00692 AC: 840

Asia WGS AF: 0.000578 AC: 2 AN: 3476

EpiCase AF: 0.00834

EpiControl AF: 0.00717

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:5

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	TRIM37: BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 15, 2018	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Aug 24, 2017	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 16, 2014	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -

Mulibrey nanism syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.38
Cadd	Uncertain	24
Dann	Uncertain	1.0
DEOGEN2	Benign	0.12	T;T;.
Eigen	Benign	0.064
Eigen_PC	Uncertain	0.29
FATHMM_MKL	Uncertain	0.95	D
MetaRNN	Benign	0.0087	T;T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	0.0	N;N;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.68	T
PROVEAN	Benign	-1.1	N;N;N
REVEL	Benign	0.057
Sift	Benign	0.090	T;T;T
Sift4G	Benign	0.088	T;T;T
Polyphen		0.057	B;B;.
Vest4		0.30
MVP		0.41
MPC		0.72
ClinPred		0.016	T
GERP RS		5.6
Varity_R		0.17
gMVP		0.57

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

Publications

LitVar

Other links and lift over

dbSNP: rs61758100; hg19: chr17-57158552; COSMIC: COSV51889288; COSMIC: COSV51889288;