rs669

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_000014.6(A2M):​c.2998A>T​(p.Ile1000Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I1000V) has been classified as Benign.

Frequency

Genomes: not found (cov: 32)

Consequence

A2M
NM_000014.6 missense

Scores

1
5
13

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.907
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]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.3828447).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
A2MNM_000014.6 linkc.2998A>T p.Ile1000Phe missense_variant Exon 24 of 36 ENST00000318602.12 NP_000005.3 P01023

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
A2MENST00000318602.12 linkc.2998A>T p.Ile1000Phe missense_variant Exon 24 of 36 1 NM_000014.6 ENSP00000323929.8 P01023
A2MENST00000542567.1 linkn.353A>T non_coding_transcript_exon_variant Exon 3 of 5 4
A2MENST00000543436.2 linkn.451+10240A>T intron_variant Intron 3 of 3 5
A2MENST00000545828.1 linkn.349-6951A>T intron_variant Intron 3 of 4 4

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
35
GnomAD4 genome
Cov.:
32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.13
BayesDel_addAF
Benign
-0.15
T
BayesDel_noAF
Benign
-0.45
CADD
Benign
19
DANN
Uncertain
0.98
DEOGEN2
Uncertain
0.45
T
Eigen
Benign
-0.25
Eigen_PC
Benign
-0.46
FATHMM_MKL
Benign
0.55
D
LIST_S2
Benign
0.80
T
M_CAP
Benign
0.035
D
MetaRNN
Benign
0.38
T
MetaSVM
Benign
-0.92
T
MutationAssessor
Pathogenic
3.2
M
PrimateAI
Benign
0.35
T
PROVEAN
Uncertain
-3.7
D
REVEL
Benign
0.051
Sift
Uncertain
0.0010
D
Sift4G
Uncertain
0.0030
D
Polyphen
0.95
P
Vest4
0.31
MutPred
0.59
Gain of methylation at K1001 (P = 0.0477);
MVP
0.76
MPC
0.68
ClinPred
0.98
D
GERP RS
0.089
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1
Varity_R
0.49
gMVP
0.51

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr12-9232268; API