rs747067557

Variant names:

• chr9-116699096-C-A
• rs747067557
• NM_012210.4:c.1354C>A

Your query was ambiguous. Multiple possible variants found:

• chr9-116699096-C-A
• chr9-116699096-C-T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_012210.4(TRIM32):​c.1354C>A​(p.Leu452Ile) variant causes a missense change. The variant allele was found at a frequency of 0.0000123 in 1,461,696 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. 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. L452F) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000012 (1 hom.)
• Consequence: TRIM32 NM_012210.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.94
• 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: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.21943122).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_012210.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TRIM32	NM_012210.4	MANE Select	c.1354C>A	p.Leu452Ile	missense	Exon 2 of 2	NP_036342.2	Q13049
	ASTN2	NM_001365068.1	MANE Select	c.2806+26675G>T		intron	N/A	NP_001351997.1	O75129-1
	TRIM32	NM_001099679.2		c.1354C>A	p.Leu452Ile	missense	Exon 2 of 2	NP_001093149.1	Q13049

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TRIM32	ENST00000450136.2	TSL:1 MANE Select	c.1354C>A	p.Leu452Ile	missense	Exon 2 of 2	ENSP00000408292.1	Q13049
	TRIM32	ENST00000373983.2	TSL:1	c.1354C>A	p.Leu452Ile	missense	Exon 2 of 2	ENSP00000363095.1	Q13049
	ASTN2	ENST00000313400.9	TSL:5 MANE Select	c.2806+26675G>T		intron	N/A	ENSP00000314038.4	O75129-1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.0000199 AC: 5 AN: 251226 AF XY: 0.0000368

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000123 AC: 18 AN: 1461696 Hom.: 1 Cov.: 31 AF XY: 0.0000234 AC XY: 17 AN XY: 727148

African (AFR) AF: 0.00 AC: 0 AN: 33462

American (AMR) AF: 0.00 AC: 0 AN: 44696

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000174 AC: 15 AN: 86250

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53410

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111890

Other (OTH) AF: 0.0000166 AC: 1 AN: 60392

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Bardet-Biedl syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.081
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.26
CADD	Benign	22
DANN	Uncertain	0.98
DEOGEN2	Benign	0.10	T
Eigen	Benign	-0.15
Eigen_PC	Benign	0.083
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.86	D
M_CAP	Benign	0.062	D
MetaRNN	Benign	0.22	T
MetaSVM	Benign	-0.49	T
MutationAssessor	Benign	0.34	N
PhyloP100		3.9
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	0.96	N
REVEL	Benign	0.25
Sift	Benign	0.15	T
Sift4G	Benign	0.061	T
Polyphen		0.0010	B
Vest4		0.19
MutPred		0.60		Gain of catalytic residue at L457 (P = 0.0212)
MVP		0.90
MPC		0.26
ClinPred		0.11	T
GERP RS		4.5
Varity_R		0.092
gMVP		0.13
Mutation Taster		=69/31	polymorphism

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: rs747067557; hg19: chr9-119461375;