rs3747835

Variant names:

• chr9-116698964-C-G
• rs3747835
• NM_012210.4:c.1222C>G

Your query was ambiguous. Multiple possible variants found:

• chr9-116698964-C-G
• chr9-116698964-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_012210.4(TRIM32):​c.1222C>G​(p.Arg408Gly) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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. R408H) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TRIM32 NM_012210.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.48
• Publications: 0 publications found

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]

ASTN2 Gene-Disease associations (from GenCC):

• autism spectrum disorder

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
• intellectual disability

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TRIM32	NM_012210.4	c.1222C>G	p.Arg408Gly	missense_variant	Exon 2 of 2	ENST00000450136.2	NP_036342.2
ASTN2	NM_001365068.1	c.2806+26807G>C		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.1222C>G	p.Arg408Gly	missense_variant	Exon 2 of 2	1	NM_012210.4	ENSP00000408292.1
ASTN2	ENST00000313400.9	c.2806+26807G>C		intron_variant	Intron 16 of 22	5	NM_001365068.1	ENSP00000314038.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Jul 14, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1222C>G (p.R408G) alteration is located in exon 2 (coding exon 1) of the TRIM32 gene. This alteration results from a C to G substitution at nucleotide position 1222, causing the arginine (R) at amino acid position 408 to be replaced by a glycine (G). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.71
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.31
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.27	T;T
Eigen	Uncertain	0.29
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.89	D;.
M_CAP	Uncertain	0.14	D
MetaRNN	Uncertain	0.71	D;D
MetaSVM	Uncertain	-0.066	T
MutationAssessor	Benign	0.90	L;L
PhyloP100		4.5
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	-2.1	N;N
REVEL	Uncertain	0.61
Sift	Benign	0.099	T;T
Sift4G	Pathogenic	0.0	D;D
Polyphen		0.92	P;P
Vest4		0.82
MutPred		0.43		Loss of MoRF binding (P = 0.0269);Loss of MoRF binding (P = 0.0269);
MVP		0.97
MPC		0.70
ClinPred		0.85	D
GERP RS		5.5
Varity_R		0.32
gMVP		0.84
Mutation Taster		=41/59	disease causing

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

Other links and lift over

dbSNP: rs3747835; hg19: chr9-119461243;