rs111033570

chr9-116699201-G-A

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM2 PP3_Strong PP5_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 (★★). Synonymous variant affecting the same amino acid position (i.e. D487D) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: TRIM32 NM_012210.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 9.56

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]

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]

ACMG classification

Verdict is Pathogenic. Variant got 16 ACMG points.

• PM1: In a repeat NHL 3 (size 40) in uniprot entity TRI32_HUMAN there are 4 pathogenic changes around while only 1 benign (80%) in NM_012210.4
• 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	UniProt
TRIM32	NM_012210.4	c.1459G>A	p.Asp487Asn	missense_variant	2/2	ENST00000450136.2
ASTN2	NM_001365068.1	c.2806+26570C>T		intron_variant		ENST00000313400.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TRIM32	ENST00000450136.2	c.1459G>A	p.Asp487Asn	missense_variant	2/2	1	NM_012210.4	P1
ASTN2	ENST00000313400.9	c.2806+26570C>T		intron_variant		5	NM_001365068.1	A2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000796 AC: 2 AN: 251384 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135916

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: 6 AN: 1461892 Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2 AN XY: 727246

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.: 33

Alfa AF: 0.0000831 Hom.: 0

Bravo AF: 0.0000113

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Sarcotubular myopathy Pathogenic:3

Pathogenic, no assertion criteria provided	literature only	OMIM	Oct 05, 2012	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	Jul 10, 2023	- -
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. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Revvity Omics, Revvity

Feb 22, 2019

- -

Myopathy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Apr 08, 2015

- -

Bardet-Biedl syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.020
Cadd	Pathogenic	33
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.56	D;D
Eigen	Pathogenic	0.69
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.93	D;.
M_CAP	Uncertain	0.19	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Uncertain	0.47	D
MutationAssessor	Uncertain	2.6	M;M
MutationTaster	Benign	1.0	A;A;A;A;A;A
PrimateAI	Pathogenic	0.83	D
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	D
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

Other links and lift over

dbSNP: rs111033570; hg19: chr9-119461480;