rs1661300

chr9-116698996-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_012210.4(TRIM32):c.1254G>A(p.Val418=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.115 in 1,613,940 control chromosomes in the GnomAD database, including 11,052 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.11 (929 hom., cov: 33)
  • Exomes 𝑓: 0.12 (10123 hom.)
• Consequence: TRIM32 NM_012210.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 0.427

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.5).
• BP6: Variant 9-116698996-G-A is Benign according to our data. Variant chr9-116698996-G-A is described in ClinVar as [Benign]. Clinvar id is 95495.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-116698996-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.427 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.14 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TRIM32	NM_012210.4	c.1254G>A	p.Val418=	synonymous_variant	2/2	ENST00000450136.2
ASTN2	NM_001365068.1	c.2806+26775C>T		intron_variant		ENST00000313400.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TRIM32	ENST00000450136.2	c.1254G>A	p.Val418=	synonymous_variant	2/2	1	NM_012210.4	P1
ASTN2	ENST00000313400.9	c.2806+26775C>T		intron_variant		5	NM_001365068.1	A2

Frequencies

GnomAD3 genomes AF: 0.106 AC: 16110 AN: 151972 Hom.: 925 Cov.: 33

Gnomad AFR AF: 0.0720

Gnomad AMI AF: 0.0967

Gnomad AMR AF: 0.0859

Gnomad ASJ AF: 0.147

Gnomad EAS AF: 0.149

Gnomad SAS AF: 0.0845

Gnomad FIN AF: 0.140

Gnomad MID AF: 0.0828

Gnomad NFE AF: 0.123

Gnomad OTH AF: 0.0936

GnomAD3 exomes AF: 0.111 AC: 27763 AN: 250520 Hom.: 1633 AF XY: 0.112 AC XY: 15113 AN XY: 135488

Gnomad AFR exome AF: 0.0696

Gnomad AMR exome AF: 0.0809

Gnomad ASJ exome AF: 0.154

Gnomad EAS exome AF: 0.137

Gnomad SAS exome AF: 0.0841

Gnomad FIN exome AF: 0.138

Gnomad NFE exome AF: 0.120

Gnomad OTH exome AF: 0.102

GnomAD4 exome AF: 0.116 AC: 169788 AN: 1461846 Hom.: 10123 Cov.: 32 AF XY: 0.116 AC XY: 84304 AN XY: 727222

Gnomad4 AFR exome AF: 0.0687

Gnomad4 AMR exome AF: 0.0823

Gnomad4 ASJ exome AF: 0.153

Gnomad4 EAS exome AF: 0.139

Gnomad4 SAS exome AF: 0.0875

Gnomad4 FIN exome AF: 0.134

Gnomad4 NFE exome AF: 0.119

Gnomad4 OTH exome AF: 0.118

GnomAD4 genome AF: 0.106 AC: 16124 AN: 152094 Hom.: 929 Cov.: 33 AF XY: 0.105 AC XY: 7812 AN XY: 74336

Gnomad4 AFR AF: 0.0719

Gnomad4 AMR AF: 0.0865

Gnomad4 ASJ AF: 0.147

Gnomad4 EAS AF: 0.149

Gnomad4 SAS AF: 0.0846

Gnomad4 FIN AF: 0.140

Gnomad4 NFE AF: 0.123

Gnomad4 OTH AF: 0.0930

Alfa AF: 0.117 Hom.: 1779

Bravo AF: 0.0996

Asia WGS AF: 0.117 AC: 406 AN: 3478

EpiCase AF: 0.124

EpiControl AF: 0.116

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jan 13, 2015	p.Val418Val in exon 2 of TRIM32: This variant is not expected to have clinical s ignificance because it does not alter an amino acid residue and is not located w ithin the splice consensus sequence. It has been identified in 12.7% (1093/8600) of European American chromosomes from a broad population by the NHLBI Exome Seq uencing Project (http://evs.gs.washington.edu/EVS; dbSNP rs1661300). -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 12, 2012	- -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 19, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Sarcotubular myopathy Benign:2

Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Bardet-Biedl syndrome 11 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Bardet-Biedl syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.50
Cadd	Benign	5.8
Dann	Benign	0.85

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: rs1661300; hg19: chr9-119461275; COSMIC: COSV57778458; COSMIC: COSV57778458;