chr9-116687369-C-T

Variant names:

• chr9-116687369-C-T
• rs558918995
• NM_012210.4:c.-94C>T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6_Moderate

The NM_012210.4(TRIM32):​c.-94C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000071 in 140,822 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0000071 (0 hom., cov: 25)
  • Exomes 𝑓: 0.0000039 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: TRIM32 NM_012210.4 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.21
• Publications: 1 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.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BP6: Variant 9-116687369-C-T is Benign according to our data. Variant chr9-116687369-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 511757.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TRIM32	NM_012210.4	c.-94C>T		5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 2	ENST00000450136.2	NP_036342.2
TRIM32	NM_012210.4	c.-94C>T		5_prime_UTR_variant	Exon 1 of 2	ENST00000450136.2	NP_036342.2
ASTN2	NM_001365068.1	c.2807-35576G>A		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.-94C>T		5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 2	1	NM_012210.4	ENSP00000408292.1
TRIM32	ENST00000450136.2	c.-94C>T		5_prime_UTR_variant	Exon 1 of 2	1	NM_012210.4	ENSP00000408292.1
ASTN2	ENST00000313400.9	c.2807-35576G>A		intron_variant	Intron 16 of 22	5	NM_001365068.1	ENSP00000314038.4

Frequencies

GnomAD3 genomes AF: 0.00000711 AC: 1 AN: 140722 Hom.: 0 Cov.: 25

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000257

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000395 AC: 1 AN: 253234 Hom.: 0 Cov.: 5 AF XY: 0.00000836 AC XY: 1 AN XY: 119636

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 4582

American (AMR) AF: 0.00 AC: 0 AN: 362

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 1498

East Asian (EAS) AF: 0.00 AC: 0 AN: 1068

South Asian (SAS) AF: 0.00 AC: 0 AN: 5086

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 80

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 516

European-Non Finnish (NFE) AF: 0.00000431 AC: 1 AN: 231754

Other (OTH) AF: 0.00 AC: 0 AN: 8288

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00000710 AC: 1 AN: 140822 Hom.: 0 Cov.: 25 AF XY: 0.00 AC XY: 0 AN XY: 68288

African (AFR) AF: 0.00 AC: 0 AN: 37484

American (AMR) AF: 0.00 AC: 0 AN: 14156

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3390

East Asian (EAS) AF: 0.00 AC: 0 AN: 4350

South Asian (SAS) AF: 0.000256 AC: 1 AN: 3900

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8816

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 288

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 65628

Other (OTH) AF: 0.00 AC: 0 AN: 1944

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Sep 19, 2017

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	16
DANN	Benign	0.92
PhyloP100		-1.2
PromoterAI		0.0018	Neutral

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs558918995; hg19: chr9-119449648;