rs111033570

Positions:

chr9-116699201-G-A

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong

The NM_012210.4(TRIM32):c.1459G>A(p.Asp487Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000041 in 1,461,892 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 Pathogenic (★★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000041 ( 0 hom. )

Consequence

TRIM32
NM_012210.4 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:9

Conservation

PhyloP100: 9.56

Variant links:

Genes affected

TRIM32 (HGNC:16380): (tripartite motif containing 32) The protein encoded by this gene is a member of the tripartite motif (TRIM) family. The TRIM motif includes three zinc-binding domains, a RING, a B-box type 1 and a B-box type 2, and a coiled-coil region. The protein localizes to cytoplasmic bodies. The protein has also been localized to the nucleus, where it interacts with the activation domain of the HIV-1 Tat protein. The Tat protein activates transcription of HIV-1 genes. [provided by RefSeq, Jul 2008]

TRIM32 links:

ASTN2 (HGNC:17021): (astrotactin 2) This gene encodes a protein that is expressed in the brain and may function in neuronal migration, based on functional studies of the related astrotactin 1 gene in human and mouse. A deletion at this locus has been associated with schizophrenia. Multiple transcript variants encoding different proteins have been found for this locus. [provided by RefSeq, May 2010]

ASTN2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.986

PP5

Variant 9-116699201-G-A is Pathogenic according to our data. Variant chr9-116699201-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 7350.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-116699201-G-A is described in Lovd as [Pathogenic]. Variant chr9-116699201-G-A is described in Lovd as [Likely_pathogenic]. Variant chr9-116699201-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TRIM32	NM_012210.4 linkuse as main transcript	c.1459G>A	p.Asp487Asn	missense_variant	2/2	ENST00000450136.2	NP_036342.2	Q13049A0A024R843
ASTN2	NM_001365068.1 linkuse as main transcript	c.2806+26570C>T		intron_variant		ENST00000313400.9	NP_001351997.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TRIM32	ENST00000450136.2 linkuse as main transcript	c.1459G>A	p.Asp487Asn	missense_variant	2/2	1	NM_012210.4	ENSP00000408292.1		Q13049
ASTN2	ENST00000313400.9 linkuse as main transcript	c.2806+26570C>T		intron_variant		5	NM_001365068.1	ENSP00000314038.4		O75129-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000796

AC:

AN:

251384

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135916

show subpopulations

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 SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000410

AC:

AN:

1461892

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

727246

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000540

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000831

Hom.:

Bravo

AF:

0.0000113

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Sarcotubular myopathy

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	Jul 10, 2023	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Oct 05, 2012	- -
Pathogenic, criteria provided, single submitter	research	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Dec 03, 2018	The homozygous p.Asp487Asn variant in TRIM32 was identified by our study in one individual with limb-girdle muscular dystrophy (LGMD). This variant has been identified in 0.001791% (2/111664) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs111033570). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. The p.Asp487Asn variant in TRIM32 has been reported in 55 Hutterite individuals with LGMD and segregated with disease in 8 affected relatives from 3 families (PMID: 11822024, 15786463). Animal models in mice have shown that this variant causes Limb-Girdle Muscular Dystrophy by lowering protein stability but not mRNA levels. Knock-in mice with this variant showed a similar neuromuscular phenotype to trim32 knock-out mice, supporting pathogenicity as a loss of function variant (PMID: 21775502). This variant has also been reported pathogenic in ClinVar by multiple submitters (Variation ID: 7350). In summary, the p.Asp487Asn variant is pathogenic. ACMG/AMP Criteria applied: PM2, PP1_Strong, PS3 (Richards 2015). -

Bardet-Biedl syndrome 11

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Jan 01, 2016

This variant was classified as: Pathogenic. This variant was detected in homozygous state. -

TRIM32-related disorder

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 02, 2024

The TRIM32 c.1459G>A variant is predicted to result in the amino acid substitution p.Asp487Asn. This variant is reported in many individuals to be causative for autosomal recessive limb-girdle muscular dystrophy type 2H (Frosk et al. 2002. PubMed ID: 11822024). Functional studies in mice suggest this variant causes destabilization and degradation of the protein and results in reduced protein levels (Kudryashova et al. 2011. PubMed ID: 21775502). This variant is reported in 0.0018% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as pathogenic. -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Revvity Omics, Revvity

Feb 22, 2019

- -

Retinal dystrophy

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg

Jan 01, 2022

- -

Bardet-Biedl syndrome

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 29, 2024

This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 487 of the TRIM32 protein (p.Asp487Asn). This variant is present in population databases (rs111033570, gnomAD 0.002%). This missense change has been observed in individual(s) with limb-girdle muscular dystrophy type 2H and sarcotubular myopathy (PMID: 11822024, 15786463, 23142638). It is commonly reported in individuals of Hutterite ancestry (PMID: 11822024, 15786463, 23142638). ClinVar contains an entry for this variant (Variation ID: 7350). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects TRIM32 function (PMID: 21775502). For these reasons, this variant has been classified as Pathogenic. -

Myopathy

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Apr 08, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.96

BayesDel_addAF

Uncertain

0.14

BayesDel_noAF

Uncertain

-0.020

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.56

D;D

Eigen

Pathogenic

0.69

Eigen_PC

Pathogenic

0.73

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.93

D;.

M_CAP

Uncertain

0.19

MetaRNN

Pathogenic

0.99

D;D

MetaSVM

Uncertain

0.47

MutationAssessor

Uncertain

2.6

M;M

PrimateAI

Pathogenic

0.83

PROVEAN

Benign

-1.5

N;N

REVEL

Uncertain

0.55

Sift

Pathogenic

0.0

D;D

Sift4G

Pathogenic

0.0

D;D

Polyphen

1.0

D;D

Vest4

0.96

MutPred

0.98

Gain of catalytic residue at T486 (P = 0.2417);Gain of catalytic residue at T486 (P = 0.2417);

MVP

0.99

MPC

0.86

ClinPred

0.92

GERP RS

5.5

Varity_R

0.69

gMVP

0.89

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over