chr12-9076794-T-C

Variant names:

• chr12-9076794-T-C
• rs200419261
• NM_000014.6:c.3494A>G

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_000014.6(A2M):​c.3494A>G​(p.Glu1165Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000245 in 1,613,934 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.00030 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00024 (1 hom.)
• Consequence: A2M NM_000014.6 missense
• Clinical Significance: Likely benign no assertion criteria provided B:1
• Conservation: PhyloP100: 0.883

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]

ACMG classification

Verdict is Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.04578674).
• BP6: Variant 12-9076794-T-C is Benign according to our data. Variant chr12-9076794-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 3058150.Status of the report is no_assertion_criteria_provided, 0 stars.
• BS2: High AC in GnomAd4 at 45 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
A2M	NM_000014.6	c.3494A>G	p.Glu1165Gly	missense_variant	Exon 28 of 36	ENST00000318602.12	NP_000005.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
A2M	ENST00000318602.12	c.3494A>G	p.Glu1165Gly	missense_variant	Exon 28 of 36	1	NM_000014.6	ENSP00000323929.8
A2M	ENST00000543436.2	n.452-8982A>G		intron_variant	Intron 3 of 3	5
A2M	ENST00000545828.1	n.349-4073A>G		intron_variant	Intron 3 of 4	4

Frequencies

GnomAD3 genomes AF: 0.000296 AC: 45 AN: 152122 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00173

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00189

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000176

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000465 AC: 116 AN: 249354 Hom.: 0 AF XY: 0.000414 AC XY: 56 AN XY: 135262

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00184

Gnomad SAS exome AF: 0.000196

Gnomad FIN exome AF: 0.00195

Gnomad NFE exome AF: 0.000283

Gnomad OTH exome AF: 0.000495

GnomAD4 exome AF: 0.000239 AC: 350 AN: 1461694 Hom.: 1 Cov.: 31 AF XY: 0.000239 AC XY: 174 AN XY: 727134

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00292

Gnomad4 SAS exome AF: 0.000197

Gnomad4 FIN exome AF: 0.00180

Gnomad4 NFE exome AF: 0.0000917

Gnomad4 OTH exome AF: 0.000315

GnomAD4 genome AF: 0.000296 AC: 45 AN: 152240 Hom.: 0 Cov.: 32 AF XY: 0.000390 AC XY: 29 AN XY: 74434

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00174

Gnomad4 SAS AF: 0.000622

Gnomad4 FIN AF: 0.00189

Gnomad4 NFE AF: 0.000176

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000227 Hom.: 0

Bravo AF: 0.000128

ExAC AF: 0.000453 AC: 55

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

A2M-related disorder Benign:1

Feb 15, 2022

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.19	T
Eigen	Benign	0.17
Eigen_PC	Benign	-0.040
FATHMM_MKL	Benign	0.38	N
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.039	D
MetaRNN	Benign	0.046	T
MetaSVM	Benign	-0.74	T
MutationAssessor	Pathogenic	3.8	H
PrimateAI	Benign	0.30	T
PROVEAN	Pathogenic	-6.5	D
REVEL	Benign	0.15
Sift	Uncertain	0.017	D
Sift4G	Benign	0.23	T
Polyphen		1.0	D
Vest4		0.23
MVP		0.83
MPC		0.50
ClinPred		0.24	T
GERP RS		5.1
Varity_R		0.54
gMVP		0.34

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs200419261; hg19: chr12-9229390; COSMIC: COSV59389774; COSMIC: COSV59389774;