rs3747835

Positions:

• chr9-116698964-C-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_012210.4(TRIM32):​c.1222C>T​(p.Arg408Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00166 in 1,614,140 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0011 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0017 (3 hom.)
• Consequence: TRIM32 NM_012210.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6 B:7 O:1
• Conservation: PhyloP100: 4.48

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]

ACMG classification

Verdict is Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.024597973).
• BP6: Variant 9-116698964-C-T is Benign according to our data. Variant chr9-116698964-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 100583.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=7, Uncertain_significance=4, not_provided=1}.
• BS2: High Homozygotes in GnomAdExome4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TRIM32	NM_012210.4	c.1222C>T	p.Arg408Cys	missense_variant	2/2	ENST00000450136.2	NP_036342.2
ASTN2	NM_001365068.1	c.2806+26807G>A		intron_variant		ENST00000313400.9	NP_001351997.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TRIM32	ENST00000450136.2	c.1222C>T	p.Arg408Cys	missense_variant	2/2	1	NM_012210.4	ENSP00000408292.1
ASTN2	ENST00000313400.9	c.2806+26807G>A		intron_variant		5	NM_001365068.1	ENSP00000314038.4

Frequencies

GnomAD3 genomes AF: 0.00116 AC: 176 AN: 152166 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000338

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000916

Gnomad ASJ AF: 0.00403

Gnomad EAS AF: 0.000387

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00178

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.00149 AC: 374 AN: 250724 Hom.: 1 AF XY: 0.00153 AC XY: 207 AN XY: 135614

Gnomad AFR exome AF: 0.000433

Gnomad AMR exome AF: 0.000463

Gnomad ASJ exome AF: 0.00557

Gnomad EAS exome AF: 0.000272

Gnomad SAS exome AF: 0.00154

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.00200

Gnomad OTH exome AF: 0.00261

GnomAD4 exome AF: 0.00171 AC: 2505 AN: 1461856 Hom.: 3 Cov.: 30 AF XY: 0.00167 AC XY: 1212 AN XY: 727226

Gnomad4 AFR exome AF: 0.000448

Gnomad4 AMR exome AF: 0.000559

Gnomad4 ASJ exome AF: 0.00578

Gnomad4 EAS exome AF: 0.000655

Gnomad4 SAS exome AF: 0.00133

Gnomad4 FIN exome AF: 0.0000375

Gnomad4 NFE exome AF: 0.00187

Gnomad4 OTH exome AF: 0.00149

GnomAD4 genome AF: 0.00115 AC: 175 AN: 152284 Hom.: 0 Cov.: 32 AF XY: 0.00105 AC XY: 78 AN XY: 74434

Gnomad4 AFR AF: 0.000337

Gnomad4 AMR AF: 0.000915

Gnomad4 ASJ AF: 0.00403

Gnomad4 EAS AF: 0.000194

Gnomad4 SAS AF: 0.00124

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00178

Gnomad4 OTH AF: 0.00236

Alfa AF: 0.00215 Hom.: 3

Bravo AF: 0.00135

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.00130 AC: 5

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00198 AC: 17

ExAC AF: 0.00143 AC: 173

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:6 Benign:7 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:4 Benign:1 Other:1

not provided, no classification provided	literature only	NEI Ophthalmic Genomics Laboratory, National Institutes of Health	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 03, 2021	Previously reported in one individual with Usher syndrome; however, no second variant in the TRIM32 gene, as would be expected with autosomal recessive inheritance, was detected in this individual (Song et al., 2011); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 22025579, 19349376) -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	May 21, 2020	- -
Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

not specified Benign:4

Likely benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jun 03, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 10, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Nov 07, 2022	Variant summary: TRIM32 c.1222C>T (p.Arg408Cys) results in a non-conservative amino acid change in the encoded protein sequence. Four of four in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0015 in 250724 control chromosomes in the gnomAD database, including 1 homozygote. The observed variant frequency is higher than the estimated maximal expected allele frequency for a pathogenic variant in TRIM32 causing Limb-Girdle Muscular Dystrophy, Autosomal Recessive phenotype (0.0013), suggesting that the variant is benign. The variant, c.1222C>T, has been reported in the literature in individuals affected with various phenotypes, however without strong evidence for causality (e.g. Song_2011, Johnson_2019, Watkins_2019). These reports do not provide unequivocal conclusions about association of the variant with Limb-Girdle Muscular Dystrophy, Autosomal Recessive. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Eight submitters have provided clinical-significance assessments for this variant in ClinVar after 2014, mostly without evidence for independent evaluation, and classified the variant as likely pathogenic (n=1), VUS (n=3), likely benign (n=4). Based on the evidence outlined above, the variant was classified as likely benign. -

Sarcotubular myopathy Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	New York Genome Center	Aug 31, 2021	- -

Bardet-Biedl syndrome 11 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genomic Research Center, Shahid Beheshti University of Medical Sciences

Dec 10, 2023

- -

Bardet-Biedl syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.26
BayesDel_addAF	Benign	0.0061	T
BayesDel_noAF	Pathogenic	0.23
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.55	D;D
Eigen	Uncertain	0.46
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.95	D;.
M_CAP	Uncertain	0.15	D
MetaRNN	Benign	0.025	T;T
MetaSVM	Uncertain	0.20	D
MutationAssessor	Benign	0.90	L;L
PrimateAI	Uncertain	0.77	T
PROVEAN	Uncertain	-2.5	D;D
REVEL	Uncertain	0.52
Sift	Uncertain	0.0010	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;D
Vest4		0.72
MVP		0.97
MPC		0.92
ClinPred		0.054	T
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.39
gMVP		0.75

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

Other links and lift over

dbSNP: rs3747835; hg19: chr9-119461243;