rs138699534

Positions:

chr9-116698263-C-T

Variant summary

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

The ENST00000450136.2(TRIM32):c.521C>T(p.Ser174Phe) variant causes a missense change. The variant allele was found at a frequency of 0.000271 in 1,614,022 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. S174S) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00019 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00028 ( 0 hom. )

Consequence

TRIM32
ENST00000450136.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:9

Conservation

PhyloP100: 4.72

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 Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TRIM32	NM_012210.4 linkuse as main transcript	c.521C>T	p.Ser174Phe	missense_variant	2/2	ENST00000450136.2	NP_036342.2
ASTN2	NM_001365068.1 linkuse as main transcript	c.2806+27508G>A		intron_variant		ENST00000313400.9	NP_001351997.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TRIM32	ENST00000450136.2 linkuse as main transcript	c.521C>T	p.Ser174Phe	missense_variant	2/2	1	NM_012210.4	ENSP00000408292	P1
ASTN2	ENST00000313400.9 linkuse as main transcript	c.2806+27508G>A		intron_variant		5	NM_001365068.1	ENSP00000314038	A2	O75129-1

Frequencies

GnomAD3 genomes

AF:

0.000191

AC:

AN:

152152

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000368

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000187

AC:

AN:

251344

Hom.:

AF XY:

0.000221

AC XY:

AN XY:

135856

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.000145

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000343

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000280

AC:

409

AN:

1461870

Hom.:

Cov.:

AF XY:

0.000276

AC XY:

201

AN XY:

727234

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.000157

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000351

Gnomad4 OTH exome

AF:

0.000166

GnomAD4 genome

AF:

0.000191

AC:

AN:

152152

Hom.:

Cov.:

AF XY:

0.000161

AC XY:

AN XY:

74306

show subpopulations

Gnomad4 AFR

AF:

0.0000483

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000368

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000371

Hom.:

Bravo

AF:

0.000223

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000581

AC:

ExAC

AF:

0.000173

AC:

EpiCase

AF:

0.000382

EpiControl

AF:

0.000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:5

Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Sep 08, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 13, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jun 07, 2024	In silico analysis indicates that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -
Uncertain significance, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Aug 14, 2020	- -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 17, 2021

The c.521C>T (p.S174F) alteration is located in exon 2 (coding exon 1) of the TRIM32 gene. This alteration results from a C to T substitution at nucleotide position 521, causing the serine (S) at amino acid position 174 to be replaced by a phenylalanine (F). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

TRIM32-related disorder

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 14, 2024

The TRIM32 c.521C>T variant is predicted to result in the amino acid substitution p.Ser174Phe. This variant has been reported in the heterozygous state in several individuals who presented with unexplained proximal muscle weakness; however, no second variant was identified in these patients and no additional evidence was provided to help determine pathogenicity of the variant (Table S1 - Johnson et al. 2019. PubMed ID: 29921608). This variant is reported in 0.033% of alleles in individuals of European (Non-Finnish) descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Sarcotubular myopathy;C1859569:Bardet-Biedl syndrome 11

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Jul 10, 2021

- -

Bardet-Biedl syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 13, 2022

This sequence change replaces serine, which is neutral and polar, with phenylalanine, which is neutral and non-polar, at codon 174 of the TRIM32 protein (p.Ser174Phe). This variant is present in population databases (rs138699534, gnomAD 0.03%). This variant has not been reported in the literature in individuals affected with TRIM32-related conditions. ClinVar contains an entry for this variant (Variation ID: 288658). 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: "Possibly Damaging"; Align-GVGD: "Class C15"). 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.25

BayesDel_addAF

Benign

-0.18

BayesDel_noAF

Benign

-0.19

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.24

T;T

Eigen

Uncertain

0.29

Eigen_PC

Uncertain

0.41

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.87

D;.

M_CAP

Benign

0.059

MetaRNN

Uncertain

0.45

T;T

MetaSVM

Benign

-0.87

MutationAssessor

Benign

1.5

L;L

MutationTaster

Benign

1.0

D;D;D;D;D;D

PrimateAI

Uncertain

0.70

PROVEAN

Benign

-2.0

N;N

REVEL

Benign

0.13

Sift

Uncertain

0.0020

D;D

Sift4G

Uncertain

0.0060

D;D

Polyphen

0.84

P;P

Vest4

0.62

MVP

0.75

MPC

0.63

ClinPred

0.089

GERP RS

5.4

Varity_R

0.24

gMVP

0.59

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