NM_004833.3:c.1030T>G

Variant names:

• chr1-159062694-A-C
• rs74689714
• NM_004833.3:c.1030T>G

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 2P and 9B. PM4 BP6 BS1 BS2

The NM_004833.3(AIM2):​c.1030T>G​(p.Ter344Gluext*?) variant causes a stop lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00197 in 1,612,214 control chromosomes in the GnomAD database, including 53 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 0.011 (24 hom., cov: 32)
  • Exomes 𝑓: 0.0011 (29 hom.)
• Consequence: AIM2 NM_004833.3 stop_lost
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: -0.0600
• Publications: 7 publications found

Genes affected

AIM2 (HGNC:357): (absent in melanoma 2) AIM2 is a member of the IFI20X /IFI16 family. It plays a putative role in tumorigenic reversion and may control cell proliferation. Interferon-gamma induces expression of AIM2. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Benign. The variant received -7 ACMG points.

• PM4: Stoplost variant in NM_004833.3 Downstream stopcodon found after 12 codons.
• BP6: Variant 1-159062694-A-C is Benign according to our data. Variant chr1-159062694-A-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 780267.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0106 (1608/151322) while in subpopulation AFR AF = 0.0362 (1493/41200). AF 95% confidence interval is 0.0347. There are 24 homozygotes in GnomAd4. There are 765 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 24 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004833.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AIM2	NM_004833.3	MANE Select	c.1030T>G	p.Ter344Gluext*?	stop_lost	Exon 6 of 6	NP_004824.1	O14862
	AIM2	NM_001348247.2		c.715T>G	p.Ter239Gluext*?	stop_lost	Exon 5 of 5	NP_001335176.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AIM2	ENST00000368130.9	TSL:1 MANE Select	c.1030T>G	p.Ter344Gluext*?	stop_lost	Exon 6 of 6	ENSP00000357112.4	O14862
	AIM2	ENST00000411768.2	TSL:5	c.1030T>G	p.Ter344Gluext*?	stop_lost	Exon 9 of 9	ENSP00000512039.1	O14862
	AIM2	ENST00000695580.1		c.1030T>G	p.Ter344Gluext*?	stop_lost	Exon 7 of 7	ENSP00000512040.1	O14862

Frequencies

GnomAD3 genomes AF: 0.0106 AC: 1604 AN: 151216 Hom.: 24 Cov.: 32

Gnomad AFR AF: 0.0362

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00441

Gnomad ASJ AF: 0.00260

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000251

Gnomad OTH AF: 0.00863

GnomAD2 exomes AF: 0.00265 AC: 664 AN: 250694 AF XY: 0.00187

Gnomad AFR exome AF: 0.0345

Gnomad AMR exome AF: 0.00168

Gnomad ASJ exome AF: 0.00239

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000106

Gnomad OTH exome AF: 0.00131

GnomAD4 exome AF: 0.00107 AC: 1569 AN: 1460892 Hom.: 29 Cov.: 30 AF XY: 0.000905 AC XY: 658 AN XY: 726764

African (AFR) AF: 0.0363 AC: 1212 AN: 33434

American (AMR) AF: 0.00173 AC: 77 AN: 44618

Ashkenazi Jewish (ASJ) AF: 0.00260 AC: 68 AN: 26114

East Asian (EAS) AF: 0.00 AC: 0 AN: 39690

South Asian (SAS) AF: 0.0000697 AC: 6 AN: 86096

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53350

Middle Eastern (MID) AF: 0.00243 AC: 14 AN: 5764

European-Non Finnish (NFE) AF: 0.0000639 AC: 71 AN: 1111486

Other (OTH) AF: 0.00201 AC: 121 AN: 60340

GnomAD4 genome AF: 0.0106 AC: 1608 AN: 151322 Hom.: 24 Cov.: 32 AF XY: 0.0103 AC XY: 765 AN XY: 73924

African (AFR) AF: 0.0362 AC: 1493 AN: 41200

American (AMR) AF: 0.00441 AC: 67 AN: 15196

Ashkenazi Jewish (ASJ) AF: 0.00260 AC: 9 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5162

South Asian (SAS) AF: 0.000417 AC: 2 AN: 4800

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10380

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.000251 AC: 17 AN: 67802

Other (OTH) AF: 0.00854 AC: 18 AN: 2108

Alfa AF: 0.00344 Hom.: 15

Bravo AF: 0.0118

ESP6500AA AF: 0.0309 AC: 136

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.00337 AC: 409

Asia WGS AF: 0.00173 AC: 6 AN: 3476

EpiCase AF: 0.000109

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	1	AIM2-related disorder (1)
-	1	-	Hereditary breast ovarian cancer syndrome (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.83	T
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.21
DANN	Benign	0.55
Eigen	Benign	-0.11
Eigen_PC	Benign	-0.59
FATHMM_MKL	Benign	0.012	N
PhyloP100		-0.060
Vest4		0.31
GERP RS		-1.9
Mutation Taster		=191/9	polymorphism (auto)

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: rs74689714; hg19: chr1-159032484;