chr9-116687354-T-C

Variant names:

• chr9-116687354-T-C
• rs886063378
• NM_012210.4:c.-109T>C

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_012210.4(TRIM32):​c.-109T>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000428 in 738,136 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00034 (0 hom., cov: 25)
  • Exomes 𝑓: 0.00045 (1 hom.)
• Consequence: TRIM32 NM_012210.4 5_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2
• Conservation: PhyloP100: 0.161
• 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 -4 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.59).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TRIM32	NM_012210.4	c.-109T>C		5_prime_UTR_variant	Exon 1 of 2	ENST00000450136.2	NP_036342.2
ASTN2	NM_001365068.1	c.2807-35561A>G		intron_variant	Intron 16 of 22	ENST00000313400.9	NP_001351997.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TRIM32	ENST00000450136.2	c.-109T>C		5_prime_UTR_variant	Exon 1 of 2	1	NM_012210.4	ENSP00000408292.1
ASTN2	ENST00000313400.9	c.2807-35561A>G		intron_variant	Intron 16 of 22	5	NM_001365068.1	ENSP00000314038.4

Frequencies

GnomAD3 genomes AF: 0.000336 AC: 46 AN: 136716 Hom.: 0 Cov.: 25

Gnomad AFR AF: 0.000111

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000721

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000245

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000593

Gnomad OTH AF: 0.000520

GnomAD4 exome AF: 0.000449 AC: 270 AN: 601330 Hom.: 1 Cov.: 8 AF XY: 0.000434 AC XY: 122 AN XY: 280892

African (AFR) AF: 0.00 AC: 0 AN: 11074

American (AMR) AF: 0.00 AC: 0 AN: 866

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3662

East Asian (EAS) AF: 0.00 AC: 0 AN: 2560

South Asian (SAS) AF: 0.00 AC: 0 AN: 11842

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 214

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1220

European-Non Finnish (NFE) AF: 0.000485 AC: 267 AN: 550304

Other (OTH) AF: 0.000153 AC: 3 AN: 19588

GnomAD4 genome AF: 0.000336 AC: 46 AN: 136806 Hom.: 0 Cov.: 25 AF XY: 0.000287 AC XY: 19 AN XY: 66294

African (AFR) AF: 0.000111 AC: 4 AN: 36056

American (AMR) AF: 0.0000720 AC: 1 AN: 13886

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3336

East Asian (EAS) AF: 0.00 AC: 0 AN: 4252

South Asian (SAS) AF: 0.00 AC: 0 AN: 3914

European-Finnish (FIN) AF: 0.000245 AC: 2 AN: 8178

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 278

European-Non Finnish (NFE) AF: 0.000593 AC: 38 AN: 64118

Other (OTH) AF: 0.000515 AC: 1 AN: 1942

Alfa AF: 0.000864 Hom.: 0

Bravo AF: 0.000227

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, single submitter

Submissions by phenotype

Sarcotubular myopathy Uncertain:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.59
CADD	Benign	17
DANN	Benign	0.57
PhyloP100		0.16
PromoterAI		0.039	Neutral

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: rs886063378; hg19: chr9-119449633;