1-159063541-A-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_004833.3(AIM2):c.950T>A(p.Leu317Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000547 in 1,461,684 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: AIM2 NM_004833.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.07

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 Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.959

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AIM2	NM_004833.3	c.950T>A	p.Leu317Gln	missense_variant	5/6	ENST00000368130.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AIM2	ENST00000368130.9	c.950T>A	p.Leu317Gln	missense_variant	5/6	1	NM_004833.3	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000119 AC: 3 AN: 251252 Hom.: 0 AF XY: 0.0000221 AC XY: 3 AN XY: 135802

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000264

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000547 AC: 8 AN: 1461684 Hom.: 0 Cov.: 31 AF XY: 0.00000550 AC XY: 4 AN XY: 727132

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000719

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 17, 2023

The c.950T>A (p.L317Q) alteration is located in exon 5 (coding exon 4) of the AIM2 gene. This alteration results from a T to A substitution at nucleotide position 950, causing the leucine (L) at amino acid position 317 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.57
BayesDel_addAF	Uncertain	0.057	T
BayesDel_noAF	Benign	-0.090
Cadd	Benign	19
Dann	Uncertain	0.99
DEOGEN2	Benign	0.32	T
Eigen	Benign	0.0040
Eigen_PC	Benign	-0.23
FATHMM_MKL	Benign	0.070	N
LIST_S2	Benign	0.49	T
M_CAP	Benign	0.012	T
MetaRNN	Pathogenic	0.96	D
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.7	M
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.31	T
PROVEAN	Pathogenic	-5.2	D
REVEL	Benign	0.28
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0040	D
Polyphen		1.0	D
Vest4		0.64
MutPred		0.85		Gain of disorder (P = 0.0304);
MVP		0.46
MPC		0.75
ClinPred		0.85	D
GERP RS		3.9
Varity_R		0.75
gMVP		0.12

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: rs753715706; hg19: chr1-159033331;