12-9069804-A-C

Position:

• chr12-9069804-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000014.6(A2M):​c.4204T>G​(p.Ser1402Ala) 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. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S1402C) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: A2M NM_000014.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.324

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:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.06824213).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
A2M	NM_000014.6	c.4204T>G	p.Ser1402Ala	missense_variant	33/36	ENST00000318602.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
A2M	ENST00000318602.12	c.4204T>G	p.Ser1402Ala	missense_variant	33/36	1	NM_000014.6	P1
A2M	ENST00000543436.2	n.452-1992T>G		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

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

Aug 22, 2023

The c.4204T>G (p.S1402A) alteration is located in exon 33 (coding exon 33) of the A2M gene. This alteration results from a T to G substitution at nucleotide position 4204, causing the serine (S) at amino acid position 1402 to be replaced by an alanine (A). 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	Benign	0.089
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.74
CADD	Benign	13
DANN	Benign	0.79
DEOGEN2	Benign	0.084	T
Eigen	Benign	-0.94
Eigen_PC	Benign	-0.93
FATHMM_MKL	Benign	0.16	N
LIST_S2	Benign	0.60	T
M_CAP	Benign	0.0044	T
MetaRNN	Benign	0.068	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	1.5	L
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-1.8	N
REVEL	Benign	0.048
Sift	Benign	0.52	T
Sift4G	Benign	0.46	T
Polyphen		0.0030	B
Vest4		0.089
MutPred		0.47		Loss of disorder (P = 0.0404);
MVP		0.63
MPC		0.18
ClinPred		0.099	T
GERP RS		1.6
Varity_R		0.14
gMVP		0.10

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: chr12-9222400;