1-159062694-A-C

Variant names:

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

Variant summary

Our verdict is Benign. Variant got -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

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

Verdict is Benign. Variant got -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 id is 780267.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Benign=1}.
• 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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 24 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AIM2	NM_004833.3	c.1030T>G	p.Ter344Gluext*?	stop_lost	Exon 6 of 6	ENST00000368130.9	NP_004824.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AIM2	ENST00000368130.9	c.1030T>G	p.Ter344Gluext*?	stop_lost	Exon 6 of 6	1	NM_004833.3	ENSP00000357112.4
AIM2	ENST00000411768.2	c.1030T>G	p.Ter344Gluext*?	stop_lost	Exon 9 of 9	5		ENSP00000512039.1
AIM2	ENST00000695580.1	c.1030T>G	p.Ter344Gluext*?	stop_lost	Exon 7 of 7			ENSP00000512040.1
AIM2	ENST00000695579.1	c.619T>G	p.Ter207Gluext*?	stop_lost	Exon 5 of 5			ENSP00000512038.1

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

GnomAD3 exomes AF: 0.00265 AC: 664 AN: 250694 Hom.: 17 AF XY: 0.00187 AC XY: 253 AN XY: 135508

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 SAS exome AF: 0.0000328

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

Gnomad4 AFR exome AF: 0.0363

Gnomad4 AMR exome AF: 0.00173

Gnomad4 ASJ exome AF: 0.00260

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000697

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000639

Gnomad4 OTH exome AF: 0.00201

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

Gnomad4 AFR AF: 0.0362

Gnomad4 AMR AF: 0.00441

Gnomad4 ASJ AF: 0.00260

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000417

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000251

Gnomad4 OTH AF: 0.00854

Alfa AF: 0.00134 Hom.: 3

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

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hereditary breast ovarian cancer syndrome Uncertain:1

Aug 01, 2020

Molecular Oncology Research Center, Barretos Cancer Hospital

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: research

- -

AIM2-related disorder Benign:1

Dec 18, 2020

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided Benign:1

Aug 08, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

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
Vest4		0.31
GERP RS		-1.9

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: rs74689714; hg19: chr1-159032484;