9-116698300-G-C

Position:

chr9-116698300-G-C

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_012210.4(TRIM32):c.558G>C(p.Gln186His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00253 in 1,614,180 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0019 ( 1 hom., cov: 33)

Exomes 𝑓: 0.0026 ( 8 hom. )

Consequence

TRIM32
NM_012210.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:6

Conservation

PhyloP100: 2.81

Variant links:

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]

TRIM32 links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.014526576).

BP6

Variant 9-116698300-G-C is Benign according to our data. Variant chr9-116698300-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 195280.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=3, Likely_benign=5}. Variant chr9-116698300-G-C is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00186 (283/152314) while in subpopulation SAS AF= 0.00415 (20/4818). AF 95% confidence interval is 0.0028. There are 1 homozygotes in gnomad4. There are 127 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 8 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TRIM32	NM_012210.4 link	c.558G>C	p.Gln186His	missense_variant	2/2	ENST00000450136.2	NP_036342.2	Q13049A0A024R843
ASTN2	NM_001365068.1 link	c.2806+27471C>G		intron_variant		ENST00000313400.9	NP_001351997.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TRIM32	ENST00000450136.2 link	c.558G>C	p.Gln186His	missense_variant	2/2	1	NM_012210.4	ENSP00000408292.1		Q13049
ASTN2	ENST00000313400.9 link	c.2806+27471C>G		intron_variant		5	NM_001365068.1	ENSP00000314038.4		O75129-1

Frequencies

GnomAD3 genomes

AF:

0.00186

AC:

283

AN:

152196

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000844

Gnomad AMI

AF:

0.00219

Gnomad AMR

AF:

0.000327

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00415

Gnomad FIN

AF:

0.000188

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.00315

Gnomad OTH

AF:

0.000959

GnomAD3 exomes

AF:

0.00188

AC:

472

AN:

251290

Hom.:

AF XY:

0.00192

AC XY:

261

AN XY:

135826

show subpopulations

Gnomad AFR exome

AF:

0.000800

Gnomad AMR exome

AF:

0.000347

Gnomad ASJ exome

AF:

0.000298

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00300

Gnomad FIN exome

AF:

0.000787

Gnomad NFE exome

AF:

0.00286

Gnomad OTH exome

AF:

0.00163

GnomAD4 exome

AF:

0.00260

AC:

3797

AN:

1461866

Hom.:

Cov.:

AF XY:

0.00259

AC XY:

1880

AN XY:

727236

show subpopulations

Gnomad4 AFR exome

AF:

0.000538

Gnomad4 AMR exome

AF:

0.000514

Gnomad4 ASJ exome

AF:

0.000306

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00312

Gnomad4 FIN exome

AF:

0.000993

Gnomad4 NFE exome

AF:

0.00295

Gnomad4 OTH exome

AF:

0.00204

GnomAD4 genome

AF:

0.00186

AC:

283

AN:

152314

Hom.:

Cov.:

AF XY:

0.00171

AC XY:

127

AN XY:

74480

show subpopulations

Gnomad4 AFR

AF:

0.000842

Gnomad4 AMR

AF:

0.000327

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00415

Gnomad4 FIN

AF:

0.000188

Gnomad4 NFE

AF:

0.00315

Gnomad4 OTH

AF:

0.000949

Alfa

AF:

0.00263

Hom.:

Bravo

AF:

0.00169

TwinsUK

AF:

0.00297

AC:

ALSPAC

AF:

0.00363

AC:

ESP6500AA

AF:

0.000908

AC:

ESP6500EA

AF:

0.00244

AC:

ExAC

AF:

0.00205

AC:

249

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.00174

EpiControl

AF:

0.00261

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:6

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2024	ASTN2: BS1 -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Apr 16, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 20, 2020	This variant is associated with the following publications: (PMID: 27323230, 27353947) -

not specified

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 18, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Nov 09, 2023	- -

Sarcotubular myopathy

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Bardet-Biedl syndrome 11

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

TRIM32-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 11, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Bardet-Biedl syndrome

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 30, 2025

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.19

BayesDel_addAF

Benign

-0.32

BayesDel_noAF

Benign

-0.23

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.52

D;D

Eigen

Benign

-0.045

Eigen_PC

Benign

-0.0098

FATHMM_MKL

Uncertain

0.97

LIST_S2

Benign

0.84

T;.

M_CAP

Benign

0.063

MetaRNN

Benign

0.015

T;T

MetaSVM

Benign

-0.98

MutationAssessor

Benign

1.8

L;L

PrimateAI

Uncertain

0.66

PROVEAN

Uncertain

-2.5

D;D

REVEL

Benign

0.25

Sift

Benign

0.087

T;T

Sift4G

Pathogenic

0.0

D;D

Polyphen

0.95

P;P

Vest4

0.56

MutPred

0.30

Loss of MoRF binding (P = 0.0953);Loss of MoRF binding (P = 0.0953);

MVP

0.81

MPC

0.84

ClinPred

0.039

GERP RS

2.5

Varity_R

0.17

gMVP

0.40

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over