rs754554333

chr9-116698910-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1 PM2

The NM_012210.4(TRIM32):c.1168C>T(p.Arg390Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000353 in 1,614,084 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R390H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000036 (0 hom.)
• Consequence: TRIM32 NM_012210.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:7
• Conservation: PhyloP100: 3.73

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 4 ACMG points.

• PM1: In a repeat NHL 1 (size 43) in uniprot entity TRI32_HUMAN there are 5 pathogenic changes around while only 1 benign (83%) in NM_012210.4
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TRIM32	NM_012210.4	c.1168C>T	p.Arg390Cys	missense_variant	2/2	ENST00000450136.2
ASTN2	NM_001365068.1	c.2806+26861G>A		intron_variant		ENST00000313400.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TRIM32	ENST00000450136.2	c.1168C>T	p.Arg390Cys	missense_variant	2/2	1	NM_012210.4	P1
ASTN2	ENST00000313400.9	c.2806+26861G>A		intron_variant		5	NM_001365068.1	A2

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152198 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

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: 0.0000441

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000199 AC: 5 AN: 251346 Hom.: 0 AF XY: 0.0000147 AC XY: 2 AN XY: 135878

Gnomad AFR exome AF: 0.0000616

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: 0.0000352

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000363 AC: 53 AN: 1461886 Hom.: 0 Cov.: 30 AF XY: 0.0000358 AC XY: 26 AN XY: 727244

Gnomad4 AFR exome AF: 0.0000896

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: 0.0000432

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152198 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74352

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000301 Hom.: 0

Bravo AF: 0.0000340

ExAC AF: 0.0000330 AC: 4

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Sep 05, 2017	The R390C variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The R390C variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). This variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jun 06, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 07, 2017	- -

Sarcotubular myopathy Uncertain:1

Uncertain significance, 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 did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Bardet-Biedl syndrome 11 Uncertain:1

Uncertain significance, 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 did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

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

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

Bardet-Biedl syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jul 12, 2022

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 390 of the TRIM32 protein (p.Arg390Cys). This variant is present in population databases (rs754554333, gnomAD 0.007%). 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: 451845). 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	Pathogenic	0.92
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	0.13
Cadd	Pathogenic	26
Dann	Uncertain	0.99
DEOGEN2	Benign	0.40	T;T
Eigen	Benign	-0.068
Eigen_PC	Benign	0.085
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.93	D;.
M_CAP	Uncertain	0.14	D
MetaRNN	Uncertain	0.70	D;D
MetaSVM	Benign	-0.81	T
MutationAssessor	Benign	1.4	L;L
MutationTaster	Benign	1.0	D;D;D;D;D;D
PrimateAI	Pathogenic	0.86	D
PROVEAN	Benign	-1.5	N;N
REVEL	Uncertain	0.37
Sift	Benign	0.044	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		0.11	B;B
Vest4		0.81
MutPred		0.72		Loss of MoRF binding (P = 0.0189);Loss of MoRF binding (P = 0.0189);
MVP		0.85
MPC		0.55
ClinPred		0.23	T
GERP RS		4.6
Varity_R		0.17
gMVP		0.79

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: rs754554333; hg19: chr9-119461189;