rs2306257

Positions:

• chr1-33165468-C-A

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BA1

The NM_018207.3(TRIM62):​c.504+3G>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.232 in 1,593,538 control chromosomes in the GnomAD database, including 44,425 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.20 (3226 hom., cov: 32)
  • Exomes 𝑓: 0.24 (41199 hom.)
• Consequence: TRIM62 NM_018207.3 splice_region, intron
• Scores: Splicing: ADA: 0.9927
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.34

Genes affected

TRIM62 (HGNC:25574): (tripartite motif containing 62) Enables identical protein binding activity; transcription coactivator activity; and ubiquitin-protein transferase activity. Involved in several processes, including negative regulation of viral transcription; positive regulation of NF-kappaB transcription factor activity; and positive regulation of antifungal innate immune response. Is active in cytoplasm. [provided by Alliance of Genome Resources, Apr 2022]

AZIN2 (HGNC:29957): (antizyme inhibitor 2) The protein encoded by this gene belongs to the antizyme inhibitor family, which plays a role in cell growth and proliferation by maintaining polyamine homeostasis within the cell. Antizyme inhibitors are homologs of ornithine decarboxylase (ODC, the key enzyme in polyamine biosynthesis) that have lost the ability to decarboxylase ornithine; however, retain the ability to bind to antizymes. Antizymes negatively regulate intracellular polyamine levels by binding to ODC and targeting it for degradation, as well as by inhibiting polyamine uptake. Antizyme inhibitors function as positive regulators of polyamine levels by sequestering antizymes and neutralizing their effect. This gene encodes antizyme inhibitor 2, the second member of this gene family. Like antizyme inhibitor 1, antizyme inhibitor 2 interacts with all 3 antizymes and stimulates ODC activity and polyamine uptake. However, unlike antizyme inhibitor 1, which is ubiquitously expressed and localized in the nucleus and cytoplasm, antizyme inhibitor 2 is predominantly expressed in the brain and testis and localized in the endoplasmic reticulum-golgi intermediate compartment. Recent studies indicate that antizyme inhibitor 2 is also expressed in specific cell types in ovaries, adrenal glands and pancreas, and in mast cells. The exact function of this gene is not known, however, available data suggest its role in cell growth, spermiogenesis, vesicular trafficking and secretion. Accumulation of antizyme inhibitor 2 has also been observed in brains of patients with Alzheimer's disease. There has been confusion in literature and databases over the nomenclature of this gene, stemming from an earlier report that a human cDNA clone (identical to ODCp/AZIN2) had arginine decarboxylase (ADC) activity (PMID:14738999). Subsequent studies in human and mouse showed that antizyme inhibitor 2 was devoid of arginine decarboxylase activity (PMID:19956990). Alternatively spliced transcript variants have been described for this gene. [provided by RefSeq, Sep 2014]

ZNF362 (HGNC:18079): (zinc finger protein 362) Predicted to enable DNA-binding transcription factor activity and RNA polymerase II cis-regulatory region sequence-specific DNA binding activity. Predicted to be involved in regulation of transcription by RNA polymerase II. Predicted to be located in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

ENSG00000279179 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.285 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TRIM62	NM_018207.3	c.504+3G>T		splice_region_variant, intron_variant		ENST00000291416.10	NP_060677.2
AZIN2	XM_047443457.1	c.*4503C>A		3_prime_UTR_variant	10/10		XP_047299413.1
TRIM62	NM_001330483.2	c.141+3G>T		splice_region_variant, intron_variant			NP_001317412.1
ZNF362	XM_047447108.1	c.-24+37019C>A		intron_variant			XP_047303064.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TRIM62	ENST00000291416.10	c.504+3G>T		splice_region_variant, intron_variant		1	NM_018207.3	ENSP00000291416.5
TRIM62	ENST00000543586.1	c.141+3G>T		splice_region_variant, intron_variant		2		ENSP00000441173.1
ENSG00000279179	ENST00000624339.1	n.2618C>A		non_coding_transcript_exon_variant	1/1	6
TRIM62	ENST00000485148.1	n.553+3G>T		splice_region_variant, intron_variant		2

Frequencies

GnomAD3 genomes AF: 0.196 AC: 29806 AN: 152120 Hom.: 3229 Cov.: 32

Gnomad AFR AF: 0.0897

Gnomad AMI AF: 0.127

Gnomad AMR AF: 0.202

Gnomad ASJ AF: 0.214

Gnomad EAS AF: 0.212

Gnomad SAS AF: 0.299

Gnomad FIN AF: 0.257

Gnomad MID AF: 0.247

Gnomad NFE AF: 0.240

Gnomad OTH AF: 0.217

GnomAD3 exomes AF: 0.228 AC: 50973 AN: 223550 Hom.: 6139 AF XY: 0.236 AC XY: 28561 AN XY: 120914

Gnomad AFR exome AF: 0.0876

Gnomad AMR exome AF: 0.181

Gnomad ASJ exome AF: 0.223

Gnomad EAS exome AF: 0.215

Gnomad SAS exome AF: 0.309

Gnomad FIN exome AF: 0.255

Gnomad NFE exome AF: 0.238

Gnomad OTH exome AF: 0.224

GnomAD4 exome AF: 0.236 AC: 340164 AN: 1441300 Hom.: 41199 Cov.: 32 AF XY: 0.239 AC XY: 170793 AN XY: 715510

Gnomad4 AFR exome AF: 0.0845

Gnomad4 AMR exome AF: 0.184

Gnomad4 ASJ exome AF: 0.222

Gnomad4 EAS exome AF: 0.199

Gnomad4 SAS exome AF: 0.310

Gnomad4 FIN exome AF: 0.255

Gnomad4 NFE exome AF: 0.238

Gnomad4 OTH exome AF: 0.223

GnomAD4 genome AF: 0.196 AC: 29810 AN: 152238 Hom.: 3226 Cov.: 32 AF XY: 0.199 AC XY: 14816 AN XY: 74418

Gnomad4 AFR AF: 0.0898

Gnomad4 AMR AF: 0.202

Gnomad4 ASJ AF: 0.214

Gnomad4 EAS AF: 0.213

Gnomad4 SAS AF: 0.298

Gnomad4 FIN AF: 0.257

Gnomad4 NFE AF: 0.240

Gnomad4 OTH AF: 0.215

Alfa AF: 0.225 Hom.: 5176

Bravo AF: 0.184

Asia WGS AF: 0.208 AC: 721 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.30
CADD	Benign	16
DANN	Benign	0.96

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.99
dbscSNV1_RF	Pathogenic	0.81
SpliceAI score (max)		0.010		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: rs2306257; hg19: chr1-33631069; COSMIC: COSV52222527;