rs139113969

Variant names:

• chr9-116698430-A-G
• rs139113969
• NM_012210.4:c.688A>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_012210.4(TRIM32):​c.688A>G​(p.Ile230Val) variant causes a missense change. The variant allele was found at a frequency of 0.0000211 in 1,614,086 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.000039 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000019 (0 hom.)
• Consequence: TRIM32 NM_012210.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:7
• Conservation: PhyloP100: 3.80
• 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.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.037371695).

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TRIM32	NM_012210.4	MANE Select	c.688A>G	p.Ile230Val	missense	Exon 2 of 2	NP_036342.2
	ASTN2	NM_001365068.1	MANE Select	c.2806+27341T>C		intron	N/A	NP_001351997.1
	TRIM32	NM_001099679.2		c.688A>G	p.Ile230Val	missense	Exon 2 of 2	NP_001093149.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TRIM32	ENST00000450136.2	TSL:1 MANE Select	c.688A>G	p.Ile230Val	missense	Exon 2 of 2	ENSP00000408292.1
	TRIM32	ENST00000373983.2	TSL:1	c.688A>G	p.Ile230Val	missense	Exon 2 of 2	ENSP00000363095.1
	ASTN2	ENST00000313400.9	TSL:5 MANE Select	c.2806+27341T>C		intron	N/A	ENSP00000314038.4

Frequencies

GnomAD3 genomes AF: 0.0000394 AC: 6 AN: 152100 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000318 AC: 8 AN: 251392 AF XY: 0.0000515

Gnomad AFR exome AF: 0.000185

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: 0.0000440

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000192 AC: 28 AN: 1461868 Hom.: 0 Cov.: 30 AF XY: 0.0000206 AC XY: 15 AN XY: 727228

African (AFR) AF: 0.000179 AC: 6 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.000174 AC: 1 AN: 5752

European-Non Finnish (NFE) AF: 0.0000171 AC: 19 AN: 1112008

Other (OTH) AF: 0.0000166 AC: 1 AN: 60396

GnomAD4 genome AF: 0.0000394 AC: 6 AN: 152218 Hom.: 0 Cov.: 32 AF XY: 0.0000538 AC XY: 4 AN XY: 74410

African (AFR) AF: 0.0000722 AC: 3 AN: 41546

American (AMR) AF: 0.0000654 AC: 1 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5154

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10600

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68014

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.0000462 Hom.: 0

Bravo AF: 0.0000189

ExAC AF: 0.0000659 AC: 8

EpiCase AF: 0.000109

EpiControl AF: 0.000178

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	3	-	not provided (3)
-	1	-	Bardet-Biedl syndrome (1)
-	1	-	Inborn genetic diseases (1)
-	1	-	Sarcotubular myopathy;C1859569:Bardet-Biedl syndrome 11 (1)
-	1	-	TRIM32-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	17
DANN	Uncertain	0.98
DEOGEN2	Benign	0.087	T
Eigen	Benign	-0.23
Eigen_PC	Benign	-0.047
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.78	T
M_CAP	Benign	0.042	D
MetaRNN	Benign	0.037	T
MetaSVM	Benign	-0.84	T
MutationAssessor	Benign	1.7	L
PhyloP100		3.8
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-0.19	N
REVEL	Benign	0.14
Sift	Benign	0.27	T
Sift4G	Uncertain	0.056	T
Polyphen		0.0	B
Vest4		0.057
MVP		0.77
MPC		0.20
ClinPred		0.070	T
GERP RS		4.2
Varity_R		0.062
gMVP		0.14
Mutation Taster		=92/8	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: rs139113969; hg19: chr9-119460709;