rs377510422

Positions:

• chr9-116698728-C-G
• chr9-116698728-C-T

Variant summary

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

The NM_012210.4(TRIM32):​c.986C>G​(p.Pro329Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,860 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: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: TRIM32 NM_012210.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 1.68

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=0.24782336).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TRIM32	NM_012210.4	c.986C>G	p.Pro329Arg	missense_variant	2/2	ENST00000450136.2	NP_036342.2
ASTN2	NM_001365068.1	c.2806+27043G>C		intron_variant		ENST00000313400.9	NP_001351997.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TRIM32	ENST00000450136.2	c.986C>G	p.Pro329Arg	missense_variant	2/2	1	NM_012210.4	ENSP00000408292.1
ASTN2	ENST00000313400.9	c.2806+27043G>C		intron_variant		5	NM_001365068.1	ENSP00000314038.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461860 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 727230

Gnomad4 AFR exome AF: 0.0000299

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

May 17, 2022

- -

Bardet-Biedl syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Apr 14, 2021

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. 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 C15"). This variant has not been reported in the literature in individuals with TRIM32-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change replaces proline with arginine at codon 329 of the TRIM32 protein (p.Pro329Arg). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and arginine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_addAF	Uncertain	0.044	T
BayesDel_noAF	Benign	-0.17
CADD	Benign	19
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.45	T;T
Eigen	Benign	-0.17
Eigen_PC	Benign	0.019
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.72	T;.
M_CAP	Benign	0.056	D
MetaRNN	Benign	0.25	T;T
MetaSVM	Benign	-0.45	T
MutationAssessor	Benign	1.7	L;L
PrimateAI	Uncertain	0.53	T
PROVEAN	Uncertain	-2.5	N;N
REVEL	Uncertain	0.39
Sift	Uncertain	0.025	D;D
Sift4G	Benign	0.10	T;T
Polyphen		0.040	B;B
Vest4		0.31
MutPred		0.27		Loss of sheet (P = 0.0181);Loss of sheet (P = 0.0181);
MVP		0.94
MPC		0.30
ClinPred		0.24	T
GERP RS		5.0
Varity_R		0.096
gMVP		0.48

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr9-119461007;