12-9077398-G-T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PP3BS2

The NM_000014.6(A2M):​c.3299C>A​(p.Thr1100Asn) variant causes a missense change. The variant allele was found at a frequency of 0.00000616 in 1,461,112 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: 0.0000062 ( 0 hom. )

Consequence

A2M
NM_000014.6 missense

Scores

4
8
7

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.83
Variant links:
Genes affected
A2M (HGNC:7): (alpha-2-macroglobulin) The protein encoded by this gene is a protease inhibitor and cytokine transporter. It uses a bait-and-trap mechanism to inhibit a broad spectrum of proteases, including trypsin, thrombin and collagenase. It can also inhibit inflammatory cytokines, and it thus disrupts inflammatory cascades. Mutations in this gene are a cause of alpha-2-macroglobulin deficiency. This gene is implicated in Alzheimer's disease (AD) due to its ability to mediate the clearance and degradation of A-beta, the major component of beta-amyloid deposits. A related pseudogene, which is also located on the p arm of chromosome 12, has been identified. [provided by RefSeq, Nov 2016]
KLRG1 (HGNC:6380): (killer cell lectin like receptor G1) Natural killer (NK) cells are lymphocytes that can mediate lysis of certain tumor cells and virus-infected cells without previous activation. They can also regulate specific humoral and cell-mediated immunity. The protein encoded by this gene belongs to the killer cell lectin-like receptor (KLR) family, which is a group of transmembrane proteins preferentially expressed in NK cells. Studies in mice suggested that the expression of this gene may be regulated by MHC class I molecules. [provided by RefSeq, Jun 2016]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

PP3
MetaRNN computational evidence supports a deleterious effect, 0.797
BS2
High AC in GnomAdExome4 at 9 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
A2MNM_000014.6 linkc.3299C>A p.Thr1100Asn missense_variant 27/36 ENST00000318602.12 NP_000005.3 P01023

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
A2MENST00000318602.12 linkc.3299C>A p.Thr1100Asn missense_variant 27/361 NM_000014.6 ENSP00000323929.8 P01023
A2MENST00000543436.2 linkn.452-9586C>A intron_variant 5
A2MENST00000545828.1 linkn.349-4677C>A intron_variant 4

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD3 exomes
AF:
0.00000401
AC:
1
AN:
249502
Hom.:
0
AF XY:
0.00000741
AC XY:
1
AN XY:
135002
show subpopulations
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:
0.00000886
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000616
AC:
9
AN:
1461112
Hom.:
0
Cov.:
31
AF XY:
0.00000413
AC XY:
3
AN XY:
726762
show subpopulations
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:
0.0000116
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000720
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32
Alfa
AF:
0.0000282
Hom.:
0
Bravo
AF:
0.00000756

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsDec 05, 2022The c.3299C>A (p.T1100N) alteration is located in exon 27 (coding exon 27) of the A2M gene. This alteration results from a C to A substitution at nucleotide position 3299, causing the threonine (T) at amino acid position 1100 to be replaced by an asparagine (N). 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
Uncertain
0.40
BayesDel_addAF
Benign
-0.098
T
BayesDel_noAF
Benign
-0.38
CADD
Benign
23
DANN
Uncertain
0.99
DEOGEN2
Benign
0.19
T
Eigen
Pathogenic
0.83
Eigen_PC
Pathogenic
0.73
FATHMM_MKL
Uncertain
0.96
D
LIST_S2
Benign
0.80
T
M_CAP
Benign
0.044
D
MetaRNN
Pathogenic
0.80
D
MetaSVM
Uncertain
0.0063
D
MutationAssessor
Pathogenic
4.3
H
PrimateAI
Uncertain
0.49
T
PROVEAN
Uncertain
-4.2
D
REVEL
Benign
0.25
Sift
Uncertain
0.0030
D
Sift4G
Uncertain
0.014
D
Polyphen
1.0
D
Vest4
0.66
MutPred
0.49
Gain of disorder (P = 0.1847);
MVP
0.77
MPC
0.77
ClinPred
1.0
D
GERP RS
4.0
Varity_R
0.79
gMVP
0.78

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1219589381; hg19: chr12-9229994; API