rs200326473

Variant names:

• chr9-116697999-T-C
• rs200326473
• NM_012210.4:c.257T>C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_012210.4(TRIM32):​c.257T>C​(p.Ile86Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000421 in 1,614,162 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.000059 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000040 (0 hom.)
• Consequence: TRIM32 NM_012210.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:6
• Conservation: PhyloP100: 7.64

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.18711442).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TRIM32	NM_012210.4	c.257T>C	p.Ile86Thr	missense_variant	Exon 2 of 2	ENST00000450136.2	NP_036342.2
ASTN2	NM_001365068.1	c.2806+27772A>G		intron_variant	Intron 16 of 22	ENST00000313400.9	NP_001351997.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TRIM32	ENST00000450136.2	c.257T>C	p.Ile86Thr	missense_variant	Exon 2 of 2	1	NM_012210.4	ENSP00000408292.1
ASTN2	ENST00000313400.9	c.2806+27772A>G		intron_variant	Intron 16 of 22	5	NM_001365068.1	ENSP00000314038.4

Frequencies

GnomAD3 genomes AF: 0.0000591 AC: 9 AN: 152198 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.000957

GnomAD3 exomes AF: 0.000163 AC: 41 AN: 251274 Hom.: 0 AF XY: 0.000155 AC XY: 21 AN XY: 135804

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.000665

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000616

Gnomad OTH exome AF: 0.00114

GnomAD4 exome AF: 0.0000404 AC: 59 AN: 1461846 Hom.: 0 Cov.: 30 AF XY: 0.0000385 AC XY: 28 AN XY: 727228

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000626

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000171

Gnomad4 OTH exome AF: 0.000149

GnomAD4 genome AF: 0.0000591 AC: 9 AN: 152316 Hom.: 0 Cov.: 32 AF XY: 0.0000403 AC XY: 3 AN XY: 74496

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000327

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.000947

Alfa AF: 0.0000868 Hom.: 0

Bravo AF: 0.000102

ExAC AF: 0.000115 AC: 14

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:3

Jul 03, 2017

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 22, 2023

Revvity Omics, Revvity

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 19, 2022

Mayo Clinic Laboratories, Mayo Clinic

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PM2 -

TRIM32-related disorder Uncertain:1

Mar 13, 2024

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The TRIM32 c.257T>C variant is predicted to result in the amino acid substitution p.Ile86Thr. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.067% of alleles in individuals of Latino descent in gnomAD, which is likely too common to be a primary cause of disease. Although we suspect that this variant may be benign, at this time, the clinical significance is uncertain due to the absence of conclusive functional and genetic evidence. -

Sarcotubular myopathy;C1859569:Bardet-Biedl syndrome 11 Uncertain:1

Mar 07, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Bardet-Biedl syndrome Uncertain:1

Oct 25, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 86 of the TRIM32 protein (p.Ile86Thr). This variant is present in population databases (rs200326473, gnomAD 0.07%). This variant has not been reported in the literature in individuals affected with TRIM32-related conditions. ClinVar contains an entry for this variant (Variation ID: 167745). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C65"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.41
BayesDel_addAF	Uncertain	0.032	T
BayesDel_noAF	Pathogenic	0.18
CADD	Uncertain	24
DANN	Benign	0.96
DEOGEN2	Benign	0.16	T;T;.
Eigen	Benign	0.095
Eigen_PC	Uncertain	0.27
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.88	D;.;D
M_CAP	Uncertain	0.20	D
MetaRNN	Benign	0.19	T;T;T
MetaSVM	Uncertain	0.085	D
MutationAssessor	Benign	1.3	L;L;.
PrimateAI	Pathogenic	0.84	D
PROVEAN	Benign	-0.98	N;N;N
REVEL	Uncertain	0.55
Sift	Uncertain	0.0030	D;D;T
Sift4G	Uncertain	0.029	D;D;T
Polyphen		0.32	B;B;.
Vest4		0.72
MVP		0.99
MPC		0.33
ClinPred		0.034	T
GERP RS		5.4
Varity_R		0.35
gMVP		0.46

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: rs200326473; hg19: chr9-119460278;